Review Article
Open access
Published: 24 March 2022

Notch signaling pathway: architecture, disease, and therapeutics

Binghan Zhou¹^na1,
Wanling Lin¹^na1,
Yaling Long¹^na1,
Yunkai Yang¹,
Huan Zhang¹,
Kongming Wu¹ &
…
Qian Chu ORCID: orcid.org/0000-0001-8192-7630¹

Signal Transduction and Targeted Therapy volume 7, Article number: 95 (2022) Cite this article

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Abstract

The NOTCH gene was identified approximately 110 years ago. Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway. NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes. NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs, the aberration of which results in cancerous and noncancerous diseases. However, recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context. In terms of cancers, NOTCH signaling can both promote and inhibit tumor development in various types of cancer. The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations. Additionally, NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers. Collectively, the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications. In this review, we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history, architecture, regulatory mechanisms, contributions to physiological development, related diseases, and therapeutic applications of the NOTCH pathway. The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.

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Introduction

The NOTCH gene was first named in studies of Drosophila melanogaster with notched wings in the 1910s^1,2,3. Homologs of NOTCH were then identified in multiple metazoans, and all these NOTCH homologs shared similar structures and signaling components^4,5,6,7. NOTCH variants were also found in ancient humans and were found to be involved in brain size control⁸. Generally, NOTCH is considered an ancient and highly conserved signaling pathway. NOTCH signaling participates in various biological processes across species, such as organ formation, tissue function, and tissue repair; thus, aberrant NOTCH signaling may cause pathological consequences.

In the past two decades, various drugs targeting NOTCH signaling have been tested in preclinical and clinical settings, yet no drug has been approved. Recent studies indicate that the NOTCH pathway is far more extensive and complicated than previously believed. As immunotherapy has revolutionized cancer treatment, NOTCH signaling and its relation with antitumor immunity have attracted the attention of scientists.

This review aims to illustrate the history, architecture, regulatory mechanisms, relation to health and diseases, and therapeutic applications of the NOTCH signaling pathway. In regard to specific behaviors of the NOTCH signaling pathway, we tried to focus on studies of mammals rather than those of other animals. We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.

A brief history of notch signaling

The NOTCH gene was first described in a study of D. melanogaster mutants with notched wings in the 1910s^1,3,4. Haploinsufficiency of NOTCH caused D. melanogaster to have notches at the end of their wings, while complete insufficiency was lethal. The discovery of this phenotype inspired the later proposed nomenclature. The D. melanogaster NOTCH gene was then isolated⁹ and sequenced¹⁰ in the 1980s, and the putative NOTCH protein was found to span the membrane and contain many epidermal growth factor (EGF)-like repeats¹¹. Studies of NOTCH signaling in D. melanogaster then increased^{12,13,14,15,16,17,18}, drawing attention to the whole signaling pathway. In 1988 and 1989, LIN-12 and GLP-1 were identified as NOTCH homologs in Caenorhabditis elegans^4,5, seemingly associated with C. elegans development^5,19,20. In 1990, XOTCH (a homolog of D. melanogaster NOTCH) was identified in Xenopus⁶, and the cDNA of the mammalian NOTCH gene was cloned⁷. Since then, research on NOTCH in other animals has gained popularity. More details of NOTCH signaling have been clarified, and as such, NOTCH has been recognized as an ancient and highly conserved signaling pathway across metazoans^{21,22,23,24,25,26}.

In 1991, the NOTCH gene was first linked to human T cell acute lymphoblastic leukemia (T-ALL). In 1997, Alagille syndrome (AGS) was found to be caused by the mutation of JAG1, which encodes a ligand of NOTCH1^27,28. AGS is a noncancerous autosomal dominant disorder characterized by the abnormal development of multiple organs. Since these discoveries, the relationship of NOTCH with human health and diseases has been extensively studied. In addition, translational studies have been performed. The first clinical trial involving NOTCH signaling was launched in 2006, using a γ-secretase inhibitor to treat patients with T-ALL or other leukemias^29,30. It was halted due to severe diarrhea, yet the results largely promoted the therapeutic targeting of NOTCH signaling. Various drugs and antibodies targeting other components of NOTCH signaling have been explored in preclinical and clinical settings, although none has yet been approved. In recent years, many new studies have been appearing, such as detailed structural analyses^31,32,33, analyses of complicated regulatory mechanisms^34,35, and analyses of diversified functions in health and diseases^36,37,38, highlighting some unexplored areas of NOTCH signaling. A brief history of NOTCH signaling is shown in Fig. 1. A strong understanding of NOTCH signaling is required; thus, more efforts are needed.

The architecture of notch signaling

The NOTCH signaling pathway has certain characteristics. Classical signaling pathways, mediated by G protein-coupled receptors (GPCRs)³⁹ and enzyme-linked receptors⁴⁰, have multiple intermediates between the membranous receptors and nuclear effectors. However, the canonical NOTCH signaling pathway has no intermediate, with receptors directly translocated into the nucleus after three cleavages^21,41,42 (Fig. 2). In addition, S2 cleavage of NOTCH receptors is triggered by interactions with ligands expressed on adjacent cells, indicating a rather narrow range of NOTCH signaling. NOTCH signaling is involved in multiple aspects of metazoans’ life⁴², including cell fate decisions, embryo and tissue development, tissue functions and repair, as well as noncancerous and cancerous diseases. Thus, understanding of the architecture of the NOTCH signaling pathway is necessary.

The receptors and ligands of NOTCH signaling

D. melanogaster has only one NOTCH receptor⁹. C. elegans has two redundant NOTCH receptors, LIN-12 and GLP-1⁴. Mammals have four NOTCH paralogs, NOTCH1, NOTCH2, NOTCH3, and NOTCH4²¹, showing both redundant and unique functions. In humans, NOTCH1, NOTCH2, NOTCH3, and NOTCH4 are located on chromosomes 9, 1, 19, and 6, respectively. After transcription and translation, NOTCH precursors are generated in the endoplasmic reticulum (ER) and then translocated into the Golgi apparatus. In the ER, the NOTCH precursors are initially glycosylated at the EGF-like repeat domain. Glycosylations include O-fucosylation, O-glucosylation, and O-GlcNAcylation, which are catalyzed by the enzymes POFUT1, POGLUT1, and EOGT1, respectively⁴³. Subsequently, in the Golgi apparatus, O-fucose is extended by the Fringe family of GlcNAc transferases, while O-glucose is extended by the xylosyltransferases GXYLT1/2 and XXYLT1^44,45,46. The glycosylation of NOTCH is vital to its stability and function. Alteration of core glycosylation enzymes severely inhibits the activity of NOTCH signaling^{47,48,49,50,51}, making these enzymes vital for further research.

The glycosylated NOTCH precursors undergo S1 cleavage in the Golgi apparatus before being transported to the cell membrane. The cleavage always occurs at a conserved site (heterodimerization domain) and is catalyzed by a furin-like protease, cutting NOTCH into a heterodimer (mature form). Here, we take mouse NOTCH1 as an example to illustrate the structure of mature NOTCH on the cell membrane.

The extracellular domain (N-terminal) contains 36 EGF-like repeats and a negative regulatory region (NRR)⁴³. The 11th and 12th EGF-like repeats usually interact with ligands⁴³, although a new study found that many more motifs of the extracellular domain are involved in ligand binding⁵². The NRR domain is composed of three cysteine-rich Lin12-NOTCH repeats (LNRs) and a heterodimerization region critical for S2 cleavage. Located after the membrane-spanning region, the intracellular RBPJ association module (RAM) domain is responsible for interacting with transcription factors in the nucleus, and seven ankyrin repeat (ANK) domains are observed in the RAM domain. Nuclear localization sequences are located on both sides of the ANK domains. At the end of the intracellular domain (C-terminus), there are conserved proline/glutamic acid/serine/threonine-rich motifs (PEST domains) that contain degradation signals and are thus critical for the stability of the NOTCH intracellular domain (NICD). Mammalian NOTCH2-4 have similar structures to NOTCH1, diverging mainly in the number of EGF-like repeats, the glycosylation level of the EGF-like repeats, and the length of the PEST domains. The level of NOTCH receptors on the cell membrane is controlled by constitutive endocytosis, which is promoted by ubiquitin ligases. An appreciable amount of NOTCH receptors are ubiquitinated and degraded in the proteosome, while the rest are expressed on the cell membrane to transmit signals.

Humans and mice have five acknowledged NOTCH ligands^21,53,54: delta-like ligand 1 (DLL1), delta-like ligand 3 (DLL3), delta-like ligand 4 (DLL4), Jagged-1 (JAG1), and Jagged-2 (JAG2), all of which present redundant and unique functions. For instance, DLL1 governs cell differentiation and cell-to-cell communication⁵⁴, DLL3 suppresses cell growth by inducing apoptosis⁵⁵, DLL4 activates NF-κΒ signaling to enhance vascular endothelial factor (VEGF) secretion and tumor metastasis⁵⁶, JAG1 enhances angiogenesis⁵⁴, and JAG2 promotes cell survival and proliferation⁵⁴.

The structures of the NOTCH ligands are partially similar to those of the receptors. The ligands are also transmembrane proteins, and the extracellular domains contain multiple EGF-like repeats, which determine the crosstalk with corresponding receptors. The levels and functions of the ligands are also controlled by ubiquitylation and endocytosis (discussed in the section “Ligand ubiquitylation”).

The canonical NOTCH signaling pathway

The mature NOTCH receptors on the cell membrane are heterodimers, with the heterodimerization domain being cleaved in the Golgi apparatus (S1 cleavage). Generally, binding to extracellular domains of NOTCH receptors allows ligands to initiate endocytosis. Such endocytosis induces receptors to change their conformation, exposing the enzymatic site for S2 cleavage⁵⁷. Receptors then experience S3 cleavage, changing into the effector form: NOTCH intracellular domain (NICD). NICD is degraded in the cytoplasm or transported into the nucleus to regulate the transcription of target genes (Fig. 2).

S2 cleavage is the only ligand-binding step and is thus vital for signal initiation. The structural basis of S2 cleavage is illustrated in Fig. 2. The S2 site (metalloprotease site) is hidden by the LNR domain in the silent phase, referred to as the “autoinhibited conformation”⁵⁸. Once bound with ligands, the receptor extends the LNR domain and exposes the S2 site for cleavage^59,60,61. The core enzymes for S2 cleavage include a disintegrin and metalloprotease 10 (ADAM 10) and its isoforms ADAM 17 and ADAMTS1^62,63,64, which are popular targets for drug discovery. The product of S2 cleavage (larger part) is composed of the transmembrane domain and the intracellular domain, which is also called NOTCH extracellular truncation (NEXT)⁶⁵.

NEXT is further cleaved at the S3 site, releasing NICD, which can be translocated into the nucleus and function as a transcription factor. The enzyme responsible for S3 cleavage is γ-secretase, which contains the catalytic subunits presenilin1 or presenilin2 (PS1 or PS2)^66,67, APH-1, PEN-2, and nicastrin (NCT)⁶⁸. However, the classical substrates for γ-secretase contain NOTCH receptors and amyloid precursor protein (APP), the successive cleavage of which is related to Alzheimer’s disease^69,70,71,72. The structural basis for γ-secretase to recognize NOTCH or APP had remained unclear until recently, when Yigong Shi’s team elucidated the structural basis^31,32. In short, the transmembrane helix of NOTCH or APP closely interacts with the surrounding transmembrane helix of PS1 (the catalytic subunit of γ-secretase); thus, the hybrid β-sheet promotes substrate cleavages, although some differences exist between NOTCH and APP⁷³. Structural information would accelerate the discovery of substrate-specific inhibitors of NOTCH and APP. Additionally, S3 cleavage can occur both on the cell membrane and in the endosome after NEXT is endocytosed, termed the endocytosis-independent model and endocytic-activation model, respectively⁷⁴.

After release from the cell membrane, NICD is translocated into the nucleus to regulate gene transcription, the mechanism of which may be related to the nuclear localization sequences of NICD and importins alpha 3, 4, and 7⁷⁵. However, the details of this translocation remain unclear. CBF-1/suppressor of hairless/Lag1 (CSL, also called recombination signal binding protein-J, RBPJ) is a ubiquitous transcription factor (TF) that recruits other co-TFs to regulate gene expression^76,77. The target genes of NOTCH signaling are largely determined by the Su (H) motif of CSL, which is responsible for DNA binding²¹. The canonical NOTCH target gene families are Hairy/Enhancer of Split (HES) and Hairy/Enhancer of Split related to YRPW motif (HEY)²¹.

In the traditional model of NICD regulating gene transcription^21,42,78,79, CSL recruits corepressor proteins and histone deacetylases (HDACs) to repress the transcription of target genes without NICD binding. NICD binding can change the conformation of the CSL-repressing complex, dissociating repressive proteins and recruiting activating partners to promote the transcription of target genes. The transcriptional coactivator Mastermind-like protein (MAML) is one of the core activating partners that can recognize the NICD/CSL interface, after which it recruits other activating partners. Drugs targeting MAML are under study.

Recently, Kimble et al. used single-molecule fluorescence in situ hybridization to study the NOTCH transcriptional program in germline stem cells of C. elegans and found that NICD dictated the probability of transcriptional firing and thus the number of nascent transcripts⁸⁰. However, NICD did not orchestrate a synchronous transcriptional response in the nucleus, in contrast to that seen in the classical model. Gomez-Lamarca et al. found similar results in D. melanogaster⁸¹. NICD promoted the opening of chromatin and enhanced the recruitment of both the NICD-containing activating CSL complex and the NICD-free repressive CSL complex. Bray et al. proposed a new model to interpret their findings. In the NOTCH-off state, chromatin is compact, and only the NICD-free (repressing) CSL complex regulates transcription. In the NOTCH-on state, chromatin is loosened and bound to both NICD-containing (activating) and NICD-free (repressive) CSL complexes. Because the number of activating complexes is greater than that of repressive complexes after NICD enters the nucleus, NICD promotes the transcription of target genes. Bray et al. further reported that nucleosome turnover occurred frequently at NOTCH-responsive regions and depended on the Brahma SWI/SNF chromatin remodeling complex⁸². Consistently, Kimble et al. found that NOTCH signaling regulated the duration of the transcriptional burst but not the intensity of signaling or the time between bursts⁸³. Oncogenic NOTCH is also considered to enhance repositioning to promote the transcription of genes, such as MYC⁸⁴. In general, the new model from Bray et al. helps explain the flexibility of NOTCH signaling, although the details still require further elucidation.

The noncanonical NOTCH signaling pathway

Pathways other than canonical signaling pathway are also able to initiate signaling, classified as noncanonical NOTCH signaling pathways. Although the mature NOTCH receptors on the cell membrane are capable of ligand binding, some are endocytosed for renewal. Endocytosed NOTCH receptors can return to the cell membrane, be degraded in lysosomes or activated in endosomes (ligand-independent activation)^74,85. Interestingly, endosome trafficking can also be regulated by NOTCH signaling⁸⁶. Endosomes have been proven to contain ADAM and γ-secretase⁸⁷. Ligand-independent activation of NOTCH signaling is vital to T cell development⁸⁸. One example of ligand-independent activation is T cell receptor (TCR)-mediated self-amplification⁸⁷. The activated TCR/CD3 complex can activate the signaling axis of LCK-ZAP70-PLCγ-PKC. PKC then activates ADAM and γ-secretase on the endosome to initiate S2 and S3 cleavage and thus NOTCH signaling. Activated NOTCH signaling can further upregulate immune-related genes to amplify the immune response.

Independent of CSL, NICD can interact with the NF-κB, mTORC, PTEN, AKT, Wnt, Hippo, or TGF-β pathways at the cytoplasmic and/or nuclear level to regulate the transcription of target genes^{34,89,90,91,92,93,94,95,96}. The crosstalk between NICD and NF-κB affects the malignant properties of cervical cancer⁸⁹, colorectal cancer⁹⁷, breast cancer⁹⁸, and small-cell lung cancer cells⁹⁹. Targeting the NF-κB pathway could be an effective way to block noncanonical NOTCH signaling.

In addition to those mentioned above, there is a newly identified mechanism of noncanonical activation. In the classical model, S3 cleavage is necessary for NOTCH receptors to release NICD and thus regulate the transcription of target genes. However, membrane-tethered NOTCH may activate the PI3K-AKT pathway, promoting the transcription of interleukin-10 and interleukin-12¹⁰⁰. In blood flow-mediated NOTCH signaling, the transmembrane domain instead of NICD recruits other partners to promote the formation of an endothelial barrier³⁵. NOTCH3 itself can promote the apoptosis of tumor endothelial cells, independent of cleavage and transcription regulation¹⁰¹. The JAG1 intracellular domain can promote tumor growth and epithelial–mesenchymal transition (EMT) without binding to NOTCH receptors¹⁰². These noncanonical mechanisms provide this ancient signaling pathway with more unique functions while massively increasing its complexity.

The mechanisms regulating NOTCH signaling

Glycosylation

The glycosylation of NOTCH receptors on specific EGF-like repeats is crucial for the maturation of receptors, which also affects signaling output. First, O-fucosylation catalyzes the enzyme Pofut1 to affect ligand binding. Elimination of Pofut1 greatly influences the ligand binding of NOTCH signaling in embryonic stem cells, lymphoid cells, and angiogenic cells of mice^103,104,105. The aberration of fringe family proteins, which catalyzes the elongation of O-fucose, can also affect ligand binding^{106,107,108,109}. Second, O-glucose of NOTCH receptors is involved in S2 cleavage. Alteration of O-glucosylation damages the proteolysis of NOTCH receptors after ligand binding^110,111. Third, the sites of O-glycosylation, such as EGF 12, are important regions for ligand binding, the loss of which decreases NOTCH signaling in T cells¹¹². Furthermore, EGF 28 might contribute to DLL1-mediated NOTCH1 signaling¹¹³. Targeting glycosylation is also thought to effectively inhibit NOTCH signaling¹¹⁴.

Receptor trafficking

After S1 cleavage, most mature NOTCH proteins are transported to the cell membrane. However, reaching the membrane does not guarantee stability. NOTCH receptors are constitutively endocytosed through a process modulated by ubiquitin ligases such as FBXW, NUMB, ASB, DTX1, NEDD4, ITCH, and CBL^{74,115,116,117,118}. Endocytosed NOTCH can be recycled to the cell membrane or trapped in the cytoplasm⁷⁴; thus, receptor trafficking can directly affect the level of NOTCH receptors on the cell membrane. Furthermore, the endocytosed NOTCH receptors in the cytoplasm can be degraded or activated. Degradation is usually initiated by the endosomal sorting complex required for transport (ESCRT) system^{119,120,121,122}, the failure of which also lays the foundation for receptor activation. However, the mechanism of ligand-independent activation remains clear^123,124,125. The balance between degradation and activation after endocytosis is closely related to downstream signaling⁷⁹. The specific distribution of receptors and ligands on the cell membrane can also influence the regional intensity of NOTCH signaling⁷⁹.

Ligand ubiquitylation

Unlike the ubiquitylation of NOTCH receptors, ubiquitylation of ligands (usually catalyzed by Neuralized (Neur) and Mindbomb (Mib)) in signal-sending cells is necessary for signaling activation. Without Neur or Mib, NOTCH signaling decreases significantly^126,127,128. One explanation is that the endocytosis of ligands promotes exposure of the NRR domain of the receptor for S2 cleavage^129,130.

Cis-inhibition

Receptors and ligands expressed on different cells can initiate signal transduction. However, receptors and ligands expressed on the same cell both inhibit and activate the whole signaling pathway, termed cis-inhibition and cis-activation^79,131. DLL3 seems to operate only in cis-inhibition^132,133. The loss of DLL3 increases NOTCH activity during T cell development in vivo¹³³. DLL1-NOTCH1 can function in both cis- and trans-activation¹³¹. Thus, the balance between cis- and trans-interactions can be vital to signaling output.

Other regulatory mechanisms

Various signals regulate the transcription of NOTCH receptors and thus the whole signaling pathway, such as AKT, RUNX1, SIRT6, CBFB, and DEC1^{134,135,136,137,138}. Many noncoding RNAs regulate the level of NOTCH receptors, such as microRNA-26a, microRNA-26b, microRNA-153, microRNA-182, and microRNA-34a^{139,140,141,142}. Nitric oxide regulates the activity of ADAM17 and USP9X and ultimately NOTCH signaling^143,144. Calzado et al. found that dual-specificity tyrosine-regulated kinase 2 (DYRK2) phosphorylated the NOTCH1 intracellular domain to promote its degradation by FBXW7¹⁴⁵. In the classical model, NOTCH signaling is prompted through the interaction between receptors and ligands in extracellular domains. However Suckling et al. found that the interaction between the C2 domain of NOTCH ligands and the phospholipid membrane of receptor-containing cells modulated NOTCH signaling.¹⁴⁶ This finding provides a possible explanation for the diversified consequences of NOTCH signaling mediated by different ligand–receptor interactions.

Notch signaling in organ development and repair

As a highly conserved signaling pathway, NOTCH deficiency leads to serious embryonic lethality. NOTCH signaling is active in the early stage of embryonic development but is maintained at a low level in the mature stage of body development. It also increases rapidly under conditions of injury or stress and is indispensable for development and injury repair (Fig. 3). First, NOTCH signaling promotes the self-renewal and dedifferentiation of stem and progenitor cells, thus maintains progenitor stemness and the stem cell pool. Among these cells, neural stem cells^147,148,149 and multipotent progenitor cells (MPCs)^150,151 are classic representatives. Different combinations of NOTCH ligands and receptors promote stem cell proliferation and inhibit terminal differentiation. Second, NOTCH signaling is involved in the selection of cell fate. Based on temporal and spatial expression of NOTCH ligands, receptors, and cell-enriched transcription factors, NOTCH signaling induces fixed differentiation of progenitor cells, such as differentiation of cardiac progenitor cells into endocardial cells and hepatoblasts into bile duct lineage cells^152,153. Furthermore, NOTCH signaling is vital to maintaining the homeostasis of the body in normal regeneration and damage repair. NOTCH signaling can rapidly regulate the dynamic transformation of cells to maintain physiological homeostasis, such as stem cells and tail cells in angiogenesis, through lateral inhibition^{154,155,156,157}. It also induces the differentiation and transformation of mature cells to promote damage repair, for example, in liver regeneration¹⁵⁸. Last, numerous ligands and receptors are involved in NOTCH signaling and have specified temporal and spatial expression in various organs and tissues, although the consequences are similar.

NOTCH and somitogenesis

The somitogenesis of vertebrates occurs in a strict order and is regulated by the segmentation clock. It is closely related to the expression of oscillating genes regulated by NOTCH, Wnt and FGF signaling^{159,160,161,162}. NOTCH signaling triggers an excitatory signal, causing presomitic mesoderm (PSM) to transition into a self-sustaining cyclic oscillation state^163,164. The gene oscillation period is consistent with the half-life of HES7¹⁶⁵ and induces lunatic fringe (Lfng) transcription. LFNG, as a glycosyl transferase that can modify the extracellular domain of NOTCH after translation and periodically blocks the cleavage of NOTCH receptors, causes the formation of cyclic NICD^166,167,168. PSM is a group of self-sustaining oscillating cells, but the synchronous oscillation between depends on the transmission of NOTCH signaling^169,170,171. LFNG inhibits the activation of NOTCH signaling in neighboring cells by regulating the function of DLL1^164,172,173. In Lfng-knockout mice, PMS oscillation fails to synchronize, but PMS oscillation amplitude and period remain unaffected¹⁷⁰. This finding further demonstrates that LFNG is a key coupling factor for synchronous oscillations between cells.

NOTCH and skeleton

In the growth and development of MPC, NOTCH signaling regulates and inhibits the production of osteoblasts¹⁵¹, chondrocytes^{174,175,176,177,178}, and osteoclasts^179,180 through different ligands and receptors (NOTCH1, NOTCH2, JAG1, DLL1) as well as the downstream target gene (SRY-related high-mobility group box 9, SOX9). In addition, the latest research shows that inhibiting glucose metabolism can guide NOTCH to regulate MPC¹⁵⁰, proving the complex role of NOTCH signaling in the skeletal microenvironment. In the mouse model, the absence of NOTCH signaling leads to depletion of MPC and nonunion of fractures¹⁸¹, consistent with the finding that activated JAG1-NOTCH signaling reduces MPC senescence and cell cycle arrest. Interestingly, using γ-secretase inhibitors intermittently and temporarily for fractures significantly promotes cartilage and bone callus formation, as well as superior strength¹⁸². This indicates that NOTCH signaling exerts its function in a temporally and spatially dependent manner.

NOTCH and cardiomyogenesis

During heart wall formation, NOTCH signaling regulates the ratio of cardiomyocytes to noncardiomyocytes by inhibiting myogenesis, further promoting atrioventricular canal remodeling and maturation, EMT development and heart valve formation^183,184,185. In the endocardium layer, the DLL4-NOTCH1-mediated Hey1/2-Bmp2-Tbx2 signaling axis is a complex negative feedback regulation loop, where overexpressed Tbx2 can in turn inhibit upstream Hey expression^{186,187,188,189}. In embryos lacking key NOTCH signaling molecules such as Notch1, Rbpj, Hey1/Heyl, or Hey2, EMT development is hindered, and endocardial cells are activated but fail to scatter and invade heart glia¹⁹⁰. NOTCH signaling affects the expression of the cadherin 5¹⁹⁰ and the TGF-β family member bone morphogenetic protein 2 (BMP2)^186,189. In addition, by downregulating VEGFR2, a key negative regulator of EMT within atrioventricular canals (AVCs), NOTCH signaling further induces EMT. Studies have found that active NOTCH1 is most highly expressed in endocardial cells at the base of the trabecular membrane. Bone morphogenetic protein 10 (BMP10)¹⁹¹ and Neuregulin 1 (NRG1)¹⁹² are key molecules of NOTCH signaling that regulate the proliferation, differentiation, and correct folding of cardiomyocytes during trabecular development.

NOTCH and the vasculature

NOTCH4 and DLL4 are specifically expressed on vascular endothelial cells (ECs)^184,193. Deficiencies in NOTCH signaling result in serious defects in the vasculature of the embryo and yolk sac during embryonic development¹⁹⁴ as well as abnormal development of multiple organs, such as the retinal vasculature^195,196 and uterine blood vessels¹⁹⁷ in rats. At the cellular level, the vascular system mainly includes ECs, pericytes and vascular smooth muscle cells (VSMCs). Under stressors such as hypoxia, resting ECs quickly transform into a state of active growth and high plasticity and then dynamically transform between tip cells (TCs) and stalk cells (SCs) through lateral inhibition rather than direct lineage changes^154,155. This cascade reaction between DLL4-mediated NOTCH signaling and VEGFA-VEGFR2 signaling induces ECs near dominant TCs to maintain a high level of NOTCH signaling, inhibiting their differentiation into TCs^198,199. NOTCH signaling activates the Wnt pathway through feedback regulation to maintain the connection between ECs, promoting vascular stability²⁰⁰. In addition, DLL4-NOTCH can maintain arterial blood–retinal barrier homeostasis by inhibiting transcytosis²⁰¹. NOTCH signaling is also important for the development of VSMCs^202,203. Blocking Notch signaling in neural crest cells, especially NOTCH2 and NOTCH3, results in vascular dysplasia, aortic defects, and even bleeding^{202,204,205,206}. The regulation of the downstream transcription factors PAX1, SCX, and SOX9 by NOTCH signaling is vital for regulating the differentiation of progenitor cells in the sclera toward VSMCs²⁰⁷.

NOTCH signaling acts decisively in the arteriovenous differentiation of endothelial cells^208,209. NOTCH signaling induces the expression of the arterial marker ephrin B2 and inhibits that of the venous marker EphB4, thereby regulating the number and diameter of arteriovenous vessels^210,211. In mice with dysfunctional mutations of NOTCH signaling molecules such as Notch1, Dll4, Hey1, or Hey2, the arterial subregion is defective, while venous differentiation is hyperactive, leading to unexpected bleeding^210,212,213. Before blood perfusion, active NOTCH signaling on the arterial side can be detected. High levels of VEGF, ERK/MAP kinase and Wnt pathway components increase DLL4 expression^214,215, and the transcription factors Fox1C and Fox2C promote DLL4 activation²¹⁶. Interestingly, ECs can sense and respond to laminar flow through NOTCH1, similar to the shear stress response, transforming the hemodynamic mechanical force into an intracellular signal, which is necessary for vascular balance^217,218.

NOTCH and the hemopoietic system

NOTCH signaling is important in the differentiation, development, and function of hematopoietic system cells, both lymphocytes and myeloid cells. In early embryonic development, the hematopoietic endothelium forms hematopoietic stem cells through NOTCH-dependent endothelial-to-hematopoietic transition²¹⁹. NOTCH signaling is fundamental in maintaining the number and stemness of hematopoietic stem cells²²⁰. In lymphocyte development, the absence of NOTCH1 or CSL in early hematopoietic progenitor cells (HPCs) leads to thymic T cell development retardation and B cell accumulation, with HES1 being the key mediator²²¹. Naïve thymocytes highly express NOTCH and immediately downregulate NOTCH1 expression once they successfully pass β-selection. Some scholars propose that NOTCH-mediated T cell development is initiated in the prethymic niche^222,223. For example, bone mesenchymal cells outside the thymus can cross-link with HPCs through NOTCH ligands on the surface to promote the generation of T cell lineages^224,225. Shreya S et al. induced the production of HSPC-derived CD7+ progenitor T cells with DLL4 and VCAM-1 in vitro engineering, and these cells further differentiated into mature T cells after thymus transplantation²²⁶. Regarding B cells, the development of splenic marginal zone B (MZB) cells depends on DLL1-NOTCH2 signaling^227,228. In addition, it was found that active NOTCH2 signaling can mediate the lineage conversion of follicular B cells into MZB cells so that mature B cell subpopulations can quickly and dynamically transform based on the needs of the immune system^229,230. The development of innate lymphoid cells (ILCs) was recently found to be NOTCH-dependent^231,232,233, and the response of different subtypes of ILCs to NOTCH signaling is heterogeneous^234,235. It is interesting that ILCs can activate MZB cells through DLL1 to enhance antibody production²³⁶. Regarding myeloid cells, NOTCH signaling is significant in the development of macrophages^237,238, dendritic cells^239,240, granulocytes²⁴¹, etc.

NOTCH and the liver

NOTCH signaling plays a key role in determining the fate of biliary tract cells and directing the correct morphogenesis of the biliary tree. Active NOTCH signaling, especially mediated by NOTCH2 and JAG1, promotes the expression of transcription factors enriched in bile duct cells, induces the differentiation of hepatocytes toward bile duct cells, and promotes the formation of the bile duct plates^152,153. The expression of SOX9, a downstream molecule of NOTCH signaling, is synchronized with the asymmetric development of the bile duct^152,242, with a mouse model of liver-specific deletion of Sox9 echoing this finding. Interestingly, delayed biliary tract development caused by liver-specific deletion of Sox9 eventually resolves in a spontaneous manner, proving that SOX9 plays a major role in timing regulation through the development of the biliary tract²⁴³.

The liver has a strong compensatory regeneration ability, where NOTCH signaling responds quickly with significant upregulation, and the transformation of hepatocytes into bile duct-like cells can be observed (Fig. 3c). Similarly, high levels of dual-phenotype hepatocytes can also be observed in liver slices of patients with early liver diseases. Additionally, in a mouse orthotopic liver transplantation model, a high level of NOTCH1 (NICD and HES1) signaling was found to have a protective effect on hepatocytes during ischemia–reperfusion injury, regulating macrophage immunity²⁴⁴. In incomplete liver injury, NOTCH signaling mediates the proliferation and differentiation of facultative progenitor cells, thereby promoting biliary tract repair. Such damage repair can be induced mainly by NOTCH2^245,246, consistent with the discovery of the role of NOTCH2 signaling in the differentiation and selection of liver progenitor cells during liver development.

NOTCH and the gastrointestinal tract

Studies have shown that NOTCH signaling prevents embryonic epithelial cells from differentiating into secretory lineages²⁴⁷, with Hes1 being the main negative regulator²⁴⁸. Highly activated NOTCH signaling promotes the differentiation of intestinal stem cells toward intestinal epithelial cells²⁴⁹. Inhibiting NOTCH signaling increases the differentiation of secretory goblet cells²⁵⁰. Additionally, the lateral inhibition of NOTCH/DLL1 and the synergy of the Wnt signaling pathway²⁵⁰ drive Paneth cell differentiation and subsequent crypt formation²⁵¹. NOTCH signaling is also essential in the lineage selection of gastric stem cells²⁵² and necessary to maintain the homeostasis of gastric antral stem cells²⁵³. Activated NOTCH signaling in differentiated mature gastric epithelial cells induces their dedifferentiation²⁵⁴. NOTCH signaling is also vital to the proliferation of pancreatic progenitor cells and their correct differentiation into mature pancreatic cells^255,256. DLL1 and DLL4 are specifically expressed in β cells, while JAG1 is expressed in α cells²⁵⁷. The DLL1-NOTCH-HES1 signaling axis promotes the growth and fate selection of multipotent pancreatic progenitor cells, while JAG1 competes with DLL1 to induce opposite effects²⁵⁸.

NOTCH and the nervous system

NOTCH signaling negatively regulates neurogenic phenotypes^{259,260,261,262}. Its absence induces differentiation of neural stem cells toward neurons at the cost of glial cell production, in both D. melanogaster and vertebrates^{263,264,265,266}. There are two mainstream models: the classic lateral inhibition model that is similar to vascular development²⁶⁷ and the model involving oscillatory expression of HES1, NEUROG2 and DLL1²⁶⁸. In addition, NOTCH signaling promotes the differentiation of most glial cell subtypes, except for oligodendrocytes. In the peripheral nervous system, the interaction between NOTCH signaling and Hairy2 is vital for the development of neural crest cells, although the specific regulatory mechanism remains unclear²⁶⁹. Active NOTCH signaling blocks the occurrence and stratification of the trigeminal nerve, leading to disorders of brain development. Furthermore, NOTCH signaling drives intestinal neural crest cells to develop into precocious glial cells in Hirschsprung disease^270,271. These results indicate that NOTCH signaling participates in neural crest differentiation, but further exploration is required²⁷².

NOTCH and other organs or systems

NOTCH signaling functions throughout lung development and the damage repair process²⁷³. Components of NOTCH signaling are highly expressed in various cells and tissues during lung development. Inhibition of NOTCH signaling or RBPJ deficiency causes defects in proximal airway differentiation, club-cell secretion inhibition, and excessive proliferation of ciliated cells and neuroendocrine cells. NOTCH2 is the main factor activating alveolar morphogenesis and maintaining airway epithelial integrity²⁷⁴. NOTCH signaling mediates the balance between the proliferation and differentiation of basal cells²⁷⁵. In damage repair, NOTCH2 in basal cells is activated, promoting the separation of cell lineages and producing secretory cells²⁷⁶.

NOTCH signaling is important in cell lineage selection, epidermal homeostasis and skin function²⁷⁷. NOTCH signaling in the skin promotes cell differentiation²⁷⁸, while NOTCH in hair follicles inhibits cell differentiation, promotes proliferation and maintains stemness. Notch signaling is also closely related to cilia cell proliferation, differentiation and morphogenesis and may be involved in asymmetric cell division in the embryonic epidermis^279,280. NOTCH signaling regulates sebaceous gland stem cells directly and indirectly. In Rbpj-deficient mice, the differentiation of sebaceous stem cells is inhibited, and the number of sebaceous glands (SGs) is reduced, with compensatory, enlarged SGs still existing²⁸¹. Many skin diseases have been found to have NOTCH signaling changes, such as hidradenitis suppurativa, psoriasis, and atopic dermatitis^282,283.

Notch signaling in noncancerous diseases

As mentioned above, NOTCH signaling is essential for body development and homeostasis, indicating that NOTCH signaling is vital for the occurrence and development of diseases. Most genetic diseases caused by NOTCH mutations have a low incidence and lack effective treatment. For example, the first discovered related disorder, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), has no effective treatment other than supportive treatment. The prognosis of only a few patients with AGS can be improved through liver transplantation, suggesting that further research is necessary. Most of the diseases caused by nonmutant NOTCH signaling abnormalities present corresponding developmental characteristics. New and interesting findings have appeared recently. For example, NOTCH signaling may be related to alcohol-associated preference, playing an important role in nonalcoholic fatty liver disease. We will now focus on the manifestations of NOTCH signaling abnormalities in diseases caused by congenital or nongenetic mutations (Table 1).

Table 1 NOTCH Signaling in Noncancerous diseases

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Diseases associated with abnormal expression of NOTCH signaling related to mutations

CADASIL

CADASIL syndrome, an arteriolar vascular disease mediated by dominant mutations in the NOTCH3 gene, is the most common hereditary cause of stroke and vascular dementia in adults^284,285. NOTCH3 is mainly expressed in VSMCs and pericytes, especially arterioles. In a study of 50 unrelated CADASIL patients, 45 with NOTCH3 pathogenic mutations²⁸⁶ presented abnormal folding of NOTCH3 and deposition of osmophilic particles near VSMCs^287,288, and cerebral arteries showed reduced lumen diameter unassociated with chronic hypertension²⁸⁹. Notch3-knockout mice show obvious structural abnormalities of arterioles and loss of vascular smooth muscle, simulating some CADASIL vascular changes, but are insufficient to constitute a complete CADASIL pathological model²⁹⁰. Attempts have been made to simulate the main pathological features of CADASIL regarding vascular damage and unique brain damage²⁹¹, such as introducing Notch3 pathogenic point mutations into large P1-derived artificial chromosomes (PACs) to construct transgenic mouse models with large genome fragments of Nothc3 pathogenic mutations²⁹² and using patient-derived induced pluripotent stem cell modeling. Evidently, NOTCH3 is pathogenic when mutated, although its underlying mechanism remains unclear.

Alagille syndrome

AGS is an autosomal dominant genetic disease caused by abnormal NOTCH signaling, with JAG1 mutations being predominant (greater than 90%) and NOTCH2 mutations being second most common (5%)^27,28,293. AGS affects multiple organs throughout the body, inducing, for example, abnormal development of the liver, heart, vasculature, bones, eyes, and maxillofacial dysplasia. Liver damage is the most prominent and is characterized by a lack of interlobular bile ducts and varying degrees of cholestasis, jaundice, and itching. AGS is one of the most important causes of chronic cholestasis in children. Symptoms ameliorate with age, yet there is still no effective treatment other than liver transplantation^294,295. These findings are consistent with the roles of JAG1 and NOTCH2 in bile duct development and morphological maintenance mentioned above. Interestingly, according to statistics, JAG1 has more than 430 mutation sites outside of mutation hotspots. Similarly, its phenotype is highly variable, and a correlation between genotype and phenotype has not yet been found^{296,297,298,299}. Thus, it remains a mystery how changes in different NOTCH receptors and ligands affect the occurrence and development of AGS. There was no research model with the characteristics of AGS until the structural defect model of the biliary tree using biopsies from AGS patients was developed, and experiments have indicated that AGS liver organoids may be a good human 3D model of AGS³⁰⁰. JAG1 homozygous mutations often lead to embryonic lethality in mice. Andersson et al. successfully constructed mice homozygous for a missense mutation (H268Q) in Jag1 (Jag1Ndr/Ndr), and these mice showed a decreased rate of embryonic lethality and recapitulation of all AGS features. Surviving mice presented with the classic absence of bile ducts and other features of AGS, including defects of the heart, vasculature, and eyes^301,302. In the pathological tissues of patients and mouse models, Joshua et al. found that the expression level of SOX9 was negatively correlated with the severity of AGS liver damage, and overexpression of SOX9 could rescue bile duct loss in Jag1+/– mouse models. One explanation is that overexpressed SOX9 can be recruited to the NOTCH2 promoter to upregulate the expression of NOTCH2 in the liver, thereby compensating for the decreased expression of the JAG1 ligand³⁰³. These new research models and related experimental data have promoted and informed further research on AGS.

Congenital scoliosis

Sporadic and familial congenital scoliosis (CS) refers to the lateral curvature of at least one spine segment caused by fetal spinal dysplasia. Studies have shown that CS is closely related to genetic factors, environmental factors, developmental abnormalities, and NOTCH signaling³⁰⁴. Several key NOTCH genes involved in the segmentation clock mechanism may explain the features of a genetic model of a rare syndrome characterized mainly by CS-spondylocostal dysostosis (SCD)^305,306.

When analyzing genes in the families of SCD patients, multiple mutation sites in DLL3 are found, and the phenotype of pyramidal dysplasia in Dll3-free mice is similar to that of SCD patients³⁰⁷. The genetic correlation between DLL3 mutation and spinal rib dysplasia has been reported³⁰⁸, and DLL3 deletion alone is unable to induce a complete SCD phenotype. In addition, Mesp2 is a downstream gene of NOTCH in somite differentiation, and abnormal expression of its 4 pairs of base repeats are closely related to SCD. Mesp2-knockout mice have spinal chondrodysplasia and serve as the current main research model^309,310. In mice, inactivation of Lfng or Hes7 can distort the development of the spine and ribs, with corresponding mutations also found in patients^311,312. Furthermore, environmental damage to genetically susceptible mice affects the penetrance and severity of the CS phenotype, especially under hypoxic conditions, providing an explanation for the family phenotypic variation of SCD³¹³.

Diseases associated with abnormal expression of NOTCH signaling not related to mutations

Nonalcoholic steatohepatitis

There is almost no NOTCH activity in hepatocytes of healthy adults, while NOTCH activity is slightly elevated in hepatocytes of people with simple steatosis and highly elevated in the hepatocytes of nonalcoholic steatohepatitis (NASH)/fibrosis patients; NOTCH activity is positively correlated with the severity of the disease. In NASH patients or high-fat diet-induced NASH mouse models, the expression of NOTCH1, NOTCH2, and HES1 is highly elevated, which activates neoadipogenesis and increases liver steatosis^314,315,316. Such abnormal NOTCH activation may mainly be induced by JAG1/NOTCH signaling triggered by intercellular TLR4³¹⁷. NOTCH-active hepatocytes can upregulate the expression of SPP1 through the downstream transcription factor SOX9, promoting secretion of osteopontin (OPN) by hepatocytes and activating hepatic stellate cells (HSCs) to induce liver fibrosis³¹⁸.

Osteoarthritis

The expression level of NOTCH signaling components is low in the articular cartilage of healthy adults but higher in osteoarthritis (OA) biopsies^319,320. After trauma, NOTCH signaling is abnormally activated in joint tissues, and its continuous activation can cause early and progressive OA-like lesions. However, transient NOTCH signaling activation helps synthesize cartilage matrix and promotes joint repair³²¹. Inhibition of NOTCH signaling was found to significantly reduce the proliferation of OA chondrocytes. However, the specific inhibition of cartilage NOTCH signaling and the decrease in MMP13 abundance in the joint can delay cartilage degeneration³²². Eventually, long-term loss of NOTCH signaling will cause cartilage homeostasis imbalance and bone destruction. The findings above suggest that Rbpj and Hes1 play a major mediating role³²³. In summary, NOTCH signaling presents duality when regulating the physiology and pathology of articular cartilage, and its effects are depending on temporal and spatial factors.

Lung-related diseases

Allergic asthma is mainly driven by the Th2 immune response, where NOTCH signaling activates the expression of the key transcription factor Gata3^324,325. Preclinical studies of γ-secretase inhibitor (GSI) have also proven that inhibiting NOTCH signaling reduces the asthma phenotype^326,327. NOTCH signaling plays an important role in promoting Th2 cell lymph node regression and lung migration³²⁸. NOTCH4 has been further proven to be vital in the occurrence of asthma. Repeated exposure to allergens can induce regulatory T cells (Tregs) to upregulate the expression of NOTCH4, dampening their immunoregulatory function and activating downstream Wnt and Hippo pathways. These factors turn Tregs into Th2 and Th17 cells, maintaining persistent allergic asthma^95,329. In addition, upregulation of JAG1 expression is found in lung tissues of patients with interstitial pulmonary fibrosis. In chronic lung injury, repeated injury promotes continuous upregulation of JAG1 by inhibiting CXCR7, leading to the continuous activation of NOTCH in surrounding fibroblasts and inducing profibrotic responses³³⁰. NOTCH3 is an important mediator of pulmonary artery remodeling in pulmonary arterial hypertension (PAH) that mediates the excessive proliferation and dedifferentiation of VSMCs³²⁹. In addition, the regulation of NOTCH1 in endothelial cells also promotes the progression of PAH^331,332. Chronic obstructive pulmonary disease (COPD) is a common lung disease associated with smoking. Studies have shown that smoking and PM2.5 exposure promote the activation of NOTCH signaling, leading to the imbalance of T cell subsets and immune disorders, thus aggravating COPD^333,334,335.

Other diseases

NOTCH signaling is a regulator of the CD4+ T cells that cause graft versus host disease (GVHD)³³⁶. Inhibition of NOTCH signaling reduces target organ injury and germinal center formation, significantly reducing the severity and mortality of GVHD^337,338. Activated NOTCH signaling can directly activate reactive T cells and promote their function³³⁹. The responsiveness of patients’ B cell receptors is also significantly enhanced by activated NOTCH signaling³⁴⁰. NOTCH signaling is also involved in regulating the glomerular filtration barrier. Abnormal activation of NOTCH1 signaling in the glomerular endothelium inhibits the expression of VE-cadherin and induces albuminuria through the transcription factors Snai1 and Erg³⁶. In adult pancreatic β cells, the abnormal activation of NOTCH signaling, especially DLL1 and DLL4, can promote β cell proliferation. A large number of naïve, dysfunctional β-cells, which proliferate but are unable to secrete insulin normally, causes glucose intolerance^257,341.

Notch signaling in cancers

NOTCH as an oncogene in cancers

NOTCH was first identified as an oncogene in T-ALL^342,343. Subsequently, the alteration of NOTCH receptors was discovered in various cancers (Fig. 4). The activation of NOTCH in breast cancer, lung adenocarcinoma, hepatocellular cancer, ovarian cancer and colorectal cancer was determined to be oncogenic⁷⁸ (Table 2). The pattern of NOTCH activation varies; for example, NOTCH can be activated by upstream signals or by structural alteration resulting from its internal mutations. Potential mechanisms of tumorigenesis include controlling the tumor-initiating cell phenotype, regulating known upstream or downstream tumor-associated signaling factors, such as MYC or P53, facilitating angiogenesis or tumor invasion, regulating the cell cycle, etc. These mechanisms will now be discussed based on cancer type.

Hematological malignancies

The oncogenic effects of NOTCH were first identified with the chromosome t (7;9) translocation of the NOTCH1 gene in T-ALL^342,343. More than 50% of T-ALL patients have NOTCH1 somatic activating mutations³⁴⁴. Transplanted hematopoietic progenitor cells with constitutive activation of NOTCH1 signaling in murine models can lead to the development of T-ALL³⁴⁵. Mechanistically, NOTCH1 activation in T-ALL might involve the extracellular heterodimerization domain (HD) and/or the C-terminal PEST domain³⁴⁴. Mutations destabilizing the HD of NOTCH1 could facilitate ligand-independent pathway activation. Furthermore, mutations disrupting the intracellular PEST domain could increase the half-life of NICD1. Many studies suggest that NOTCH1 may induce the expression of MYC by regulating its enhancer N-Me and play a key role in the initiation and maintenance of T-ALL³⁴⁶. The interaction of NOTCH1 and PTEN promotes anabolic pathways in T-ALL³⁴⁷. In addition to these synergistic effects, NOTCH1 can directly regulate the expression of specific lncRNAs, such as LUNAR1, which is essential for the malignant proliferation of T-ALL cells³⁴⁸. Additionally, NOTCH signaling regulates the progression of the T-ALL cell cycle via the expression of the G(1) phase proteins cyclin D3, CDK4, and CDK6³⁴⁹. In recent years, activating mutations of NOTCH3 independent of NOTCH1 mutations have also been found in several cases³⁵⁰, providing novel insights into NOTCH mutations in T-ALL.

In addition, activating mutations in NOTCH have been identified in other hematological malignancies. Approximately 58% of splenic marginal zone lymphoma cases have activating NOTCH mutations, termed NNK-SMZLs, and such cases are related to inferior survival³⁵¹. In a B cell chronic lymphocytic leukemia (B-CLL) murine model, dysfunction of NOTCH signaling reduces morbidity, while activation of NOTCH signaling increases the survival and apoptosis resistance of B-CLL cells³⁵². In diffuse large B-cell lymphoma (DLBCL), NOTCH also participates in the tumor growth through the FBXW7-NOTCH-CCL2/CSF1 axis³⁵³. Although NOTCH plays an oncogenic role in most hematological malignancies, it inhibits the growth and survival of acute myeloid leukemia (AML), and consistent activation of NOTCH1-4 leads to AML growth arrest and caspase-dependent apoptosis³⁵⁴.

Lung adenocarcinoma

In lung adenocarcinoma (LUAD) patients, high expression of NOTCH1 and NOTCH3 has been detected^355,356. This alteration involves loss of NUMB expression, which increases NOTCH activity, and gain-of-function mutations of the NOTCH1 gene³⁵⁷. In vivo and in vitro studies confirmed that NOTCH1-3 contributes to the initiation and progression of LUAD^358,359,360, indicating that NOTCH acts as an oncogene in LUAD. The tumorigenesis effect might involve activating mutations of downstream genes regulating the tumor-initiating cell phenotype. First, NOTCH3 is a key driver gene in KRAS-mediated LUAD that activates PKCι-ELF3-NOTCH3 signaling to regulate asymmetric cell division in tumor initiation and maintenance processes³⁶¹. Second, coactivation of NOTCH1 and MYC increases the frequency of NICD1-induced adenoma formation and enables tumor progression and metastases in a mouse model³⁶⁰. In addition, NOTCH1 activation in KRAS-induced LUAD suppresses p53-mediated apoptosis³⁵⁸. However, NOTCH mutations have opposite effects in LUAD and squamous cell carcinoma (SCC) according to recent studies³⁶². Since most studies of NOTCH are conducted in undistinguished non-small-cell lung cancer (NSCLC) patients, the specific effect of NOTCH in LUAD needs further research.

Colorectal cancer

Physiologically, NOTCH signaling is essential for the development and homeostasis of normal intestinal epithelia; for example, NOTCH signaling regulates the differentiation of colonic goblet cells and stem cells^363,364. In human colorectal cancer (CRC) tissues, significant upregulation of NOTCH ligands (DLL1, DLL3, DLL4, JAG1, and JAG2) and aberrant activation of the NOTCH receptor (NOTCH1) are found^365,366. Such abnormal NOTCH activation is associated with poorer prognosis and metastasis of CRC³⁶⁷. Inhibiting NOTCH by miR-34a and Numb suppresses the proliferation and differentiation of colon cancer stem cells³⁶⁸, indicating that NOTCH activation is a trigger of colon cancer development. Abnormal NOTCH signaling promotes the invasion and metastasis of CRC cells, possibly through the NOTCH-DAB1-ABL-TRIO pathway, EMT and TGF-β-dependent neutrophil effects³⁶⁹. On the one hand, NOTCH promotes CRC invasion by inducing ABL tyrosine kinase activation and phosphorylation of the RHOGEF protein TRIO³⁷⁰. On the other hand, active NOTCH signaling promotes the occurrence of metastasis by reshaping the tumor microenvironment and regulating EMT-associated transcription factors such as SLUG and SNAIL^367,371,372. In conclusion, the NOTCH pathway induces EMT in colon cancer with TP53 deletion^370,373,374.

Breast cancer

Studies of NOTCH signaling in epithelial tumors were first performed in breast cancer^{375,376,377,378}. Upregulation of non-mutated NOTCH signaling-related proteins, such as NOTCH1 and JAG1, is associated with poor prognosis in breast cancer³⁷⁹. In mouse models, mutations in Notch1 and Notch4 mediated by mouse mammary tumor viruses can promote epithelial mammary tumorigenesis^380,381. Moreover, functionally recurrent rearrangements of NOTCH gene families are found in breast cancer, of which cell lines are sensitive to NOTCH inhibitors³⁸². In HER2-expressing breast cancer cells, NOTCH activation seems to be associated with cytotoxic chemotherapy resistance³⁸³. Such an abnormal increase in NOTCH signaling expression is believed to be related to a lack of NUMB expression³⁸⁴, and its promoting effect on breast cancer tumorigenesis might be exerted from multiple aspects. First, NOTCH signaling maintains the stemness of breast cancer cells and promotes initiation^385,386. Second, NOTCH signaling shapes elements of the breast cancer microenvironment, especially tumor-associated macrophages (TAMs), which is related to the innate immune phenotype³⁸⁷. In addition, NOTCH can be activated by the ASPH-Notch axis, providing materials for the synthesis/release of prometastatic exosomes in breast cancer³⁸⁸.

Ovarian cancer

In ovarian cancer, approximately 23% of patients have NOTCH signaling alterations³⁸⁹. NOTCH1 and NOTCH3 have been discovered to directly promote the occurrence and development of ovarian cancer^{389,390,391,392}. Overexpression of NOTCH3 is related to cell hyperproliferation and apoptosis inhibition, as well as tumor metastasis and recurrence^393,394. As NOTCH3 is positively correlated with JAG1 and JAG2 expression in ovarian cancer, the carcinogenic function of NOTCH3 is potentially mediated by JAG1-NOTCH3 activation³⁹⁵, and dynamin-dependent endocytosis is required. Notch2/Notch3 and other NOTCH signaling molecules have achieved certain effects by inhibiting Jag1 in a mouse ovarian cancer model^396,397. In addition, through methylation of the VEGFR2 promoter, NOTCH signaling facilitates angiogenesis in ovarian cancer mediated by VEGFR2 negative feedback³⁹⁸.

Hepatocellular carcinoma

NOTCH signaling is a pathogenic factor in NASH, yet its role in hepatocellular carcinoma (HCC) is less well defined³⁹⁹. Approximately 30% of human HCC samples have activated NOTCH signaling, which in mice promotes the formation of liver tumors⁴⁰⁰. Recently, NOTCH activation was found in some HCC subtypes with unique molecular and clinicopathologic features and was found to be associated with poor prognosis³⁹⁹. NOTCH activation is also related to the activation of insulin-like growth factor 2, which contributes to hepatocarcinogenesis⁴⁰¹. Furthermore, NOTCH activation facilitates EMT progression and metastasis in HCC⁴⁰². On the other hand, NOTCH activation slows HCC growth and can predict HCC patient prognosis⁴⁰³. Mutations in the NOTCH target gene HES5 in HCC samples can present both protumorigenic and antitumorigenic functions⁴⁰⁴. A close relationship between the function of NOTCH1 and the P53 mutation state has been reported, in which NOTCH1 activation increases the invasiveness of P53 WT HCC cells while decreasing that of P53-mutated HCC cells⁴⁰⁵. Although showing contradictory functions in HCC, NOTCH is still mainly considered an oncogenic factor.

Glioma

NOTCH signaling used to be considered oncogenic in glioma, in which it maintains brain cancer stem cells⁴⁰⁶. Knockdown of NOTCH ligands in human brain microvascular endothelial cells (hBMECs) or inhibition of NOTCH signaling with a γ-secretase inhibitor in glioma constrains tumor growth both in vitro and in vivo^407,408. Notch1 has potentially oncogenic effects in the brain in association with other oncogenic hits, such as p53 loss in a medulloblastoma mouse model⁴⁰⁹. Positive feedback of NOTCH1-SOX2 enhances glioma stem cell invasion along white matter tracts⁴¹⁰. NOTCH also induces the expression of lncRNA and TUG1 to maintain the stemness of glioma stem cells and suppress differentiation⁴¹¹. Moreover, NOTCH1 signaling promotes the invasion and growth of glioma-initiating cells by modulating the CXCL12/CXCR4 chemokine system⁴¹². However, NOTCH suppresses forebrain tumor subtypes. Inactivation of Rbpj, Notch1, or Notch2 receptors accelerates tumor growth in a mouse model⁴¹³. Such a subtype-specific effect of NOTCH in glioma might be related to cooperation with P53. Overall, NOTCH signaling acts either as an oncogenic factor or a tumor suppressor in different glioma subtypes, and the mechanisms need further exploration⁴¹⁴.

Other cancers

Adenoid cystic carcinoma (ACC), commonly found in the salivary gland, frequently features activating NOTCH1 and NOTCH2 mutations^{415,416,417,418}. NOTCH1 inhibitors have significant antitumor efficacy in both ACC patients and patient-derived xenograft (PDX) models^419,420. Upregulation of MYB signaling through NOTCH mutation and amplification might also be a potential driving mechanism of ACC⁴²¹. Activated NOTCH1 also produces CD133(+) ACC cells, regarded as cancer stem-like cells in ACC. In clear cell renal cell carcinoma (CCRCC), the overexpression of NOTCH ligands and receptors is observed in tumor tissues. Activated NOTCH1 leads to dysplastic hyperproliferation of tubular epithelial cells, and treatment involving a γ-secretase inhibitor leads to CCRCC cell inhibition both in vitro and in vivo⁴²².

NOTCH as a tumor suppressor in cancers

NOTCH may be involved in many cancers as a protumor effector, but it can also act as a tumor suppressor in others, such as squamous cell carcinoma (SCC) and neuroendocrine tumors⁴²³ (Fig. 4, Table 2). Antitumor mechanisms include regulating transcription factors with malignant effects, activating downstream suppressive genes, inhibiting the cell cycle, etc. In light of studies regarding its antitumor effects, the traditional opinion of NOTCH as an oncogene has been challenged⁴¹⁴.

Neuroendocrine tumors

NOTCH is now believed to act as a suppressor in neuroendocrine tumors (NETs), including tumors derived from the thyroid, neuroendocrine cells of the gut, the pancreas, and the respiratory system⁴²⁴. Small-cell lung cancer (SCLC) is the most common type of pulmonary NET, with nearly 25% of human SCLC cases presenting inactivation of NOTCH target genes in one comprehensive genomic profiling analysis⁴²⁵. A recent study used a multiomics approach to analyze the dynamic changes during transdifferentiation from NSCLC to SCLC⁴²⁶, which is a special feature of acquired resistance to EGFR-TKIs in LUAD. This study found that the downregulation of NOTCH signaling was essential for the initial cell state switch of LUAD cells⁴²⁶, indicating that NOTCH plays a tumor-suppressive role in SCLC. Furthermore, high DLL3 expression is frequently detected in SCLC and lung carcinoid tumors^{55,426,427,428}, which downregulates NOTCH signaling via cis-inhibition. In an SCLC mouse model, activation of Notch1 or Notch2 reduces the expression of synaptophysin and Ascl1, inhibiting the cell cycle process^429,430. Likewise, in human medullary thyroid cancer (MTC) tumor samples, NOTCH1 protein is undetectable, while the expression of NICD1 inhibits MTC cell proliferation⁴³¹. In an analysis of gastroenteropancreatic NET tumor specimens, reduced NOTCH expression and mutated components were found^432,433. Mechanistically, some studies consider that such an antitumorigenesis effect might be mediated by the NOTCH-ASCL1-RB-P53 tumor suppression pathway^434,435, while others hold that activated NOTCH could inhibit cell growth via cell cycle arrest associated with upregulated P21^431,436. NOTCH could also mark and initiate deprogramming in rare pulmonary NET cells that serve as stem cells in SCLC⁴³⁷. Considering the suppressor effect of NOTCH in NETs, drugs targeting DLL3 have been tested in SCLC, with promising results witnessed in preclinical trials (discussed in detail in the following sections).

Squamous cell cancers

In SCC specimens, inactivated NOTCH1-3 has been detected^438,439,440. 40% of head and neck squamous cell cancer (HNSCC) cases are found to have inactivated NOTCH1^441,442. In cutaneous squamous cell cancer (cSCC) and its adjacent normal tissue, NOTCH receptors are also frequently found mutated, resulting in loss of function or downregulation⁴⁴³. Similarly, malfunction of NOTCH1 and NOTCH2 was found in lung squamous cell carcinoma (LUSC) patients⁴⁴⁴. This negative relation between NOTCH and carcinogenesis was also found in bladder⁴⁴⁵, esophageal^446,447, and cervical SCC⁴⁴⁸. In an SCC mouse model, genomic aberrations in NOTCH1 induced by mutagenic agents result in an increased tumor burden^449,450. Dominant-negative Mastermind-like 1 (DNMAML1), an inhibitor of canonical NOTCH transcription, promotes de novo SCC formation⁴⁵¹. Moreover, a study of γ-secretase inhibitors in Alzheimer’s disease (AD) patients showed that inhibiting S3 cleavage in NOTCH might increase the risk of nonmelanoma skin cancer⁴⁵². Most studies of the mutated form of NOTCH in SCCs show that NOTCH function relies deeply on context; for example, NOTCH function can be affected by factors such as the P53 pathway and the intrinsic transcription-repressive protein RBP-Jκ⁴⁴⁰. The detailed regulatory mechanism is unclear, although some studies believe that NOTCH signaling maintains the CD133 phenotype in stem cells of SCCs⁴⁵³. Furthermore, decreased NOTCH1 expression also dysregulates cell cycle-associated genes in SCCs such as LUSC³⁶².

Pancreatic ductal carcinoma

NOTCH mutation is common in PDAC⁴⁵⁴. NOTCH1 can inhibit the formation of pancreatic intraepithelial neoplasia (PanIN) in a PDAC mouse model⁴⁵⁵. Additionally, Notch1 loss is required progression in a Kras-induced PDAC mouse model⁴⁵⁶, suggesting its role as a tumor suppressor gene. However, previous studies suggest that NOTCH plays an oncogenic role in the occurrence and development of PDAC^457,458,459. NOTCH signaling has been found to be activated in PDAC, which causes the growth of premalignant PDAC cells⁴⁵⁷.

Table 2 NOTCH Signaling in Cancers

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NOTCH signaling in the tumor microenvironment

The tumor microenvironment (TME) refers to the factors surrounding tumor cells during their generation and development, including various immune cells, fibroblasts, extracellular matrix (ECM) components, and vasculature^460,461. NOTCH signaling is deeply involved in regulating the diversified components of the TME⁴⁶² (Fig. 5).

NOTCH signaling in immune cells

Generally, immune cells in the TME can be classified into two clusters, inflammatory (tumor-suppressive) immune cells and immune-suppressive (tumor-promoting) immune cells⁴⁶³, and NOTCH signaling plays important roles in both cell types. NOTCH signaling not only determines the differentiation of immune cells but also regulates their functional states.

Dendritic cells

In a mouse model with CD11c lineage-specific deletion of Dll1, CD8+ T cells are decreased, while regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) are increased, leading to faster tumor growth⁴⁶⁴. Administration of a DLL1 analog can reverse Dll1 deficiency-induced immunosuppression⁴⁶⁴. However, mice with CD11c lineage-specific deletion of JAG2 do not show this phenotype, and administration of a JAG1-competitive antagonist reduces Tregs, improving antitumor immunity⁴⁶⁴. In the colitis-associated colorectal cancer (CRC) model, Notch2 deficiency in the CD11c lineage impairs dendritic cell (DC) differentiation, reduces DC migration, and suppresses antigen-presenting capacity⁴⁶⁵, mirroring those conditions found in a pioneering study in nontumoral conditions²⁴⁰. In conclusion, both NOTCH ligands (DLL1) and receptors (NOTCH2) play positive roles in DC function, while JAG2 on DCs plays negative roles. As NOTCH signaling is crucial for DC differentiation and maturation, two research groups developed a method to increase the yield of cDC1s from mouse and human hematopoietic progenitor cells by employing DLL1-expressing stroma^466,467, which might be applicable for autologous DC-based vaccination⁴⁶⁸.

CD8+ T cells

First, the DLL1-NOTCH1/2 axis is necessary for naïve CD8+ T cells to differentiate into effector T cells because it regulates the expression of the transcription factor eomesodermin (EOMES) and effector molecules (granzyme B and perforin)^{469,470,471,472}. Selective activation of DLL1/4-NOTCH inhibits tumor growth⁴⁷³. In addition, NOTCH signaling is involved in the TCR-mediated self-amplification of T cells (section “The noncanonical NOTCH signaling pathway”). The activated TCR/CD3 complex can directly promote the cleavage of NOTCH receptors on endosomes, initiating the response of CD8+ T cells independent of NOTCH ligands⁸⁷. As adenosine A2A receptor (A2AR) stimulation decreases TCR-mediated NOTCH activity⁴⁷⁴, inhibiting A2AR might help boost the CD8+ T cell response⁴¹. Second, NOTCH signaling is essential for the persistence and function of human lung tissue-resident memory T cells (TRM cells)⁴⁷⁵, thus assisting long tumor control^476,477,478. Third, NOTCH signaling is also reported to have a negative impact on CD8+ T cells. NOTCH signaling upregulates the PD-1 expression of CD8+ T cells, thus promoting their exhaustion⁴⁷⁹. Inhibition of the NOTCH signaling pathway decreases the PD-1 level of CD8+ T cells and promotes the cytotoxicity of tumor-infiltrating CD8+ T cells in CRC patients⁴⁸⁰. Collectively, NOTCH receptors on CD8+ T cells play positive roles in antitumor immunity, paving the way for displaying NOTCH receptors on T cells for autologous T cell transfer therapy. One challenge in current chimeric antigen receptor-T (CAR-T) cell therapy is the exhaustion of transferred CAR-T cells. In light of this challenge, researchers designed new CAR-T cells with a synthetic NOTCH (synNOTCH) receptor loaded on the cell membrane^481,482. These synNOTCH CAR-T cells not only promote the immune response but also maintain a higher fraction of effector T cells in the memory state^481,482, which suggests the utility of such a strategy for next-generation CAR-T cell engineering^483,484.

CD4+ T cells, B cells, and NK cells

Different ligand-mediated NOTCH signaling pathways also induce further differentiation and functions of CD4+ T cells⁴⁸⁵. DLL-mediated NOTCH signaling promotes type1 T helper cell (Th1) differentiation, while JAG1/2-mediated NOTCH signaling induces the differentiation of Th2 and Tregs^485,486,487. Blocking NOTCH signaling with a GSI deeply impaired the generation and immunosuppressive function of Tregs⁴⁸⁸. However, Charbonnier et al. found that deletion of NOTCH components enhanced the immune-suppressive functions of Tregs, while transgenic overexpression of the NOTCH1 intracellular domain impaired Treg fitness⁴⁸⁹. As NOTCH signaling plays diversified roles in the generation and function of Tregs, distinguishing different signal-sending cells, ligands and receptors might be of much significance. DLL1-NOTCH2 signaling also mediates the development of splenic MZB cells. NK cells isolated from cancer patients show lower expression levels of NOTCH receptors than those of healthy donors⁴⁹⁰.

Tumor-associated macrophages

First, NOTCH signaling is necessary for the terminal differentiation of tumor-associated marcrophages (TAMs)⁴⁹¹. The deletion of CSL in monocyte lineages abrogates TAM differentiation and functions⁴⁹¹. A recent study found that inhibition of NOTCH signaling indeed impeded the differentiation of monocyte-derived TAMs while increasing the differentiation of Kupffer cell-like TAMs (kclTAMs) by upregulating Wnt/β-catenin signaling⁴⁹². Second, NOTCH signaling participates in the recruitment of TAMs in basal-like breast cancer (BLBC)³⁸⁷. JAG1-NOTCH1/2/3 signaling in BLBC cells promotes the secretion of IL-1β and CCL2, recruiting TAMs into the TME. Simultaneously, the TAMs secrete transforming growth factor-β (TGF-β) to induce JAG1 expression in BLBC cells via the TGFβR1-SMAD2/3 pathway. This paracrine loop contributes to the suppressive immune microenvironment of BLBC and also indicates therapeutic opportunities. Third, NOTCH signaling regulates the polarization of TAMs between M1-like (tumor-suppressive) and M2-like (tumor-promoting) phenotypes. JAG1-NOTCH signaling between endocrine-resistant breast cancer cells and TAMs results in the differentiation of TAMs toward an M2-like phenotype, contributing to resistance to endocrine therapy⁴⁹³. NOTCH signaling mediates M2 polarization of TAMs in diffuse large B cell lymphoma (DLBCL) through the CREBBP/EP300-FBXW7-NOTCH-CCL2/CSF1 pathway³⁵³. However, NOTCH signaling is also reported to promote the M1 polarization of macrophages in anti-infection immunity^494,495 and anticancer immunity^496,497. In terms of transplanted tumors, macrophages with insufficient NOTCH signaling exhibit M2 phenotypes, while macrophages with forced activation of NOTCH signaling show M1 phenotypes and promote tumor shrinkage^496,497.

Myeloid-derived suppressor cells

Similar to its role in TAMs, NOTCH signaling also participates in the differentiation^498,499,500, chemotaxis⁵⁰¹, and function of MDSCs. Regarding functional regulation, tumor-derived factors upregulate JAG1/2 on MDSCs through NFkB-p65 signaling, forming a suppressive immune microenvironment⁵⁰². Anti-JAG1/2 antibodies decrease the accumulation and tolerogenic activity of MDSCs and inhibit the expression of the immunosuppressive factors arginase I and iNOS, thus restoring defective antitumor immunity⁵⁰². In addition to its immune-regulatory functions, NOTCH signaling also participates in the MDSC-mediated regulation of tumor cell behaviors. Bone marrow-derived CD11b+JAG2+ cells infiltrate primary colorectal tumors and initiate the EMT program of tumor cells, thus promoting tumor metastasis⁵⁰³. Polymorphonuclear-MDSCs (PMN-MDSCs) interact with circulating tumor cells (CTCs) through NOTCH signaling, enhancing CTC dissemination and metastatic potency⁵⁰⁴. MDSCs activate NOTCH signaling in tumor cells to endow them with stem cell-like qualities in breast cancer^505,506. In summary, NOTCH signaling mainly promotes the immune-suppressive and tumor-promoting functions of MDSCs; thus, targeting JAG1/2 might be a promising strategy.

Tumor-associated neutrophils

Jackstadt et al. reported that NOTCH1 signaling in CRC cells could promote the secretion of CXCL5 and TGF-β, recruiting tumor-associated neutrophils (TANs) to drive metastasis³⁶⁷. Additionally, JAG2-expressing TANs impair the cytotoxicity of CD8+ T cells via NOTCH signaling⁵⁰⁷.

NOTCH signaling in cancer-associated fibroblasts and the extracellular matrix

On the one hand, NOTCH signaling participates in the differentiation of cancer-associated fibroblasts (CAFs). In keratinocyte tumors, loss of NOTCH signaling promotes CAF differentiation and further tumor initiation^508,509,510. However, in colon and prostate cancer, CAF differentiation is initiated by elevated NOTCH signaling^511,512. In addition, CAFs activate NOTCH signaling in cancer cells to promote various malignant behaviors, including the cancer stem cell phenotype^513,514,515, chemotherapy resistance⁵¹⁶, metastasis^517,518, and disease recurrence⁵¹⁹. ECM components, such as fibulin-1⁵²⁰, fibulin-3⁵²¹, microfibril-associated glycoprotein 2 (MAGP2)⁵²², and laminin α5 (LAMA5)⁵²³, can also regulate the intensity of NOTCH signaling in cancer cells. Furthermore, activated NOTCH signaling in PDAC cells is reported to reshape the ECM through exosomes, thus promoting lung metastasis⁵²⁴.

NOTCH signaling in the tumor vasculature

The balance of DLL4 and JAG1 endothelial expression is important for tumor vasculature generation. When DLL4 is inhibited, small blood vessel branches sprout, tumor vascular density increases, vascular function remains poor, overall tumor perfusion decreases, and tumor growth is inhibited. Such effects on the tumor vasculature thus could be employed for antitumor therapy^525,526. After binding to NOTCH receptors, JAG1 promotes angiogenesis by competing with DLL4. In breast cancer, JAG1 has been confirmed to induce tumor angiogenesis and tumor growth^527,528. Additionally, NOTCH activation in ECs promotes lung metastasis, while endothelial NOTCH1 activation in the liver reduces intercellular adhesion molecule-1 expression and endothelial tumor cell adhesion and retention, thereby reducing liver metastasis^528,529. During radiotherapy, endothelial NOTCH1 activation protects tumor vessels from radiotherapy-induced damage and regulates endothelial-mesenchymal transition⁵³⁰. Surprisingly, NOTCH3 acts as a receptor-dependent receptor in the endothelium to induce endothelial cell apoptosis and can be blocked by JAG1⁵²⁶. Furthermore, NOTCH blockade in VSMC-DA suppresses the contractile phenotype and promotes the secretory phenotype of VSMC-DA cells, thereby enhancing tumor cell invasion and proliferation⁵²⁶.

Notch-targeted therapies

As a classical and fundamental signaling pathway in humans, NOTCH is crucial for the development and homeostasis of most tissues. Deregulated NOTCH signaling leads to various diseases, as presented above. For decades, NOTCH-targeting therapeutic strategies have been searched, with many drugs being studied in the preclinical stage or tested in clinical trials. NOTCH signaling has been investigated as a therapeutic target for the treatment of cancer, most recently in the fields of immunity and inflammatory disorders. In the following chapter, research on ongoing or completed NOTCH-targeted therapeutics will be presented according to the employed mechanism (Table 3).

Table 3 Drugs targeting the NOTCH signaling pathway assessed in clinical trials

Full size table

Cleavage inhibitors

S1 cleavage

Precursors of NOTCH receptors require S1 cleavage in the Golgi before integration with their ligands. Sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) is an important accessory factor in this process that modulates ATP-dependent calcium pumps⁵³¹. Malfunction of SERCAs impairs NOTCH signaling, especially that of mutant NOTCH1⁵³². Mutant NOTCH1 protein acts as an oncogene in T-ALL as well as other malignant tumors⁵³³, making SERCAs potential therapeutic targets⁵³⁴. Thapsigargin, a guaianolide compound of plant origin that inhibits SERCAs in mammalian cells, has been tested in breast cancer and leukemia at the preclinical stage^535,536,537. CPA⁵³⁴, CAD204520⁵³⁸ and other small molecular inhibitors of SERCA with lower off-target toxicity have been investigated in the laboratory, yet no surprising results have been reported to encourage further clinical trials.

S2 cleavage

S2 cleavage occurs in the ligand–receptor binding domain, mediating ectodomain shedding and regulating the transmission speed of NOTCH signaling^539,540. A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) or ADAM17 (also called tumor necrosis factor-alpha convertase, TACE) can be exploited to prevent S2 cleavage and NOTCH signaling transmission, as they are key enzymes of S2 cleavage^{62,541,542,543}. Similar to SERCA inhibitors, ADAM inhibitors target the entire NOTCH pathway. Small molecule drugs targeting ADAMs have been studied in non-small-cell lung cancer⁵⁴⁴, hepatocellular carcinoma⁵⁴⁵, renal carcinoma⁵⁴⁶, breast cancer⁵⁴⁷, and systemic sclerosis⁵⁴⁸. Some of these inhibitors have shown anti-NOTCH activities in vitro and in animal experiments, yet no clinical trial has been initiated.

S3 cleavage

The canonical signal transmission of NOTCH signaling from outisde the cell to inside the cell relies heavily on S3 cleavage mediated by the γ-secretase complex^549,550, suggesting that it is promising to modulate the function of γ-secretase for treatment.

γ-Secretase inhibitors

γ-Secretase inhibitors (GSIs) were first tested as a treatment for Alzheimer’s disease (AD) in clinical trials because γ-secretase contributes to catalyzing the production of β-amyloid peptide. Unfortunately, the study was terminated shortly after it began because of serious NOTCH-associated adverse events such as gastrointestinal symptoms, infections, and nonmelanoma skin cancers⁵⁵¹. Since then, researchers have attempted to treat cancer with GSIs to disrupt NOTCH signaling. In preclinical studies, GSIs are widely studied as a treatment for cancer, showing antitumor activity in diverse tumor types, such as breast cancer^552,553, hepatocellular carcinoma^554,555, non-small-cell lung cancer⁵⁵⁶, colorectal cancer⁵⁵⁷, prostate cancer⁵⁵⁸, and gliomas⁵⁵⁹. Cancer patients were first documented to receive GSI treatment in 2006, with one of six patients with T-ALL or acute myeloid leukemia receiving MK-0752 in a phase I clinical trial; the trial showed a promising 45% reduction in mediastinal mass after 28 days, although the treatment was paused because of severe diarrhea (NCT00100152). Other drugs, including PF-03084014⁵⁶⁰, RO4929097^561,562, BMS-986115⁵⁶³, LY900009⁵⁶⁴, LY3039478⁵⁶⁵, and MK-0752^566,567, have emerged in phase I trials, all of which have shown antitumor efficacy. However, most have presented dose-limiting toxicities. To date, only RO4929097 and PF-03084014 have entered phase II trials. Unfortunately, although the adverse events (AEs) were well tolerated, only 1 patient among 32 patients with metastatic melanoma treated with RO4929097 achieved a partial response⁵⁶⁸. Similar outcomes occurred in platinum-resistant epithelial ovarian cancer and colorectal cancer, with no objective response among valid participants^569,570; thus, few agents have entered phase III/IV clinical trials. PF-03084014, also called nirogacestat, achieved more promising outcomes in patients with desmoid tumors (aggressive fibromatosis) than RO4929097, as 29% of the 15 patients experienced a confirmed partial response that was maintained for more than 2 years⁵⁷¹. A phase III clinical trial for nirogacestat has already been registered, although the trial has yet to begin (NCT03785964).

In addition to cancer, because NOTCH plays a critical role in the differentiation of Th cells, GSIs have also been studied in allergic diseases such as asthma⁵⁷². NOTCH signaling regulates Th1 and Th2 responses in allergic pulmonary inflammation, indicating its promising targetability in immune disease.

γ-Secretase modulators

γ-Secretase modulators (GSMs) were originally studied in AD⁵⁷³. As a superior option to GSIs, GSMs aim to modify the catalytic activity of γ-secretase rather than to nonselectively inhibit it, enabling partial NOTCH signaling function to be maintained and thus theoretically ameliorating adverse events⁵⁷⁴. The selective inhibitor MRK-560 targeting PSEN1, an important catalytic subclass of γ-secretase complexes, has been proven to effectively decrease mutant NOTCH1 processing and cause cell cycle arrest in T-ALL without associated gut toxicity⁵⁷⁵. GSMs are only applied in AD as drugs that are designed to modulate amyloid-β (Aβ) peptide generation without impacting the function of NOTCH^576,577.

Antibody-drug conjugates

Given the severe adverse events of inhibiting the overall NOTCH pathway, antibodies targeting different receptors and ligands have been explored to achieve precise targeting of NOTCH signaling^578,579. There are five ligands and four receptors in the NOTCH signaling pathway²¹. Although the roles of each component are not completely clear, functions related to specific diseases have been confirmed, making them potential targets⁴¹.

Antibodies against ligands

JAG1

As reported previously, the upregulated expression of JAG1 enhances proliferation and angiogenesis in various malignant tumors, including adrenocortical carcinoma⁵⁸⁰, breast cancer³⁷⁹, and prostate cancer⁵⁸¹. These pathological mechanisms make JAG1 a promising target, and monoclonal antibodies against JAG1 have been studied in breast cancer⁵⁸², ovarian cancer³⁹⁶, and other malignant tumors⁵⁸². 15D11, one of the most promising fully human monoclonal antibodies against JAG1, has been studied at the preclinical stage; 15D11 increases chemotherapy sensitivity, reduces neoplastic growth in bone metastases, and, most importantly, causes minor adverse effects⁵⁸³.

DLL3

DLL3 is an inhibitory ligand of NOTCH signaling that is highly upregulated and aberrantly expressed on the cell surface of small-cell lung cancer (SCLC) and other high-grade neuroendocrine tumors as a key driving gene^55,584,585. DLL3-directed antibody-drug conjugates (ADCs) induce durable and safe responses in SCLC and large-cell neuroendocrine cancer (LCNEC) PDX tumor models⁴²⁷. Positive results inspired further clinical trials. In 2017, Charles M Rudin et al. first reported their encouraging results of rovalpituzumab tesirine (Rova-T); 11 of 60 assessable patients with SCLC or LCNEC had confirmed objective responses, and the objective response rate (ORR) was relatively higher in patients with high DLL3 expression. Although 38% of 74 patients suffered severe drug-related AEs, the AEs could be controlled⁵⁷⁹. Unfortunately, further phase II and III studies failed to achieve their efficacy end points. Relapsed/refractory SCLC patients receiving Rova-T after at least two lines of therapy achieved a median overall survival (mOS) time of only 5.6 months, and the ORR was 12.4%⁵⁸⁶. A study of Rova-T as a maintenance therapy after first-line platinum-based chemotherapy was terminated shortly after it began due to a lack of survival benefit⁵⁸⁷. Compared with concurrent standard second-line chemotherapy, Rova-T showed shorter OS and lower safety⁵⁸⁸. Attempts to combine chemotherapy and immune checkpoint inhibitors also failed, with extra toxicities and moderate efficacy^579,589. Although the abovementioned studies failed to meet their expected end points, complete responses appeared in nearly every study, indicating that this therapeutic strategy has good prospects. However, strategies to stratify patients and appropriate biomarkers should be explored. Researchers have also attempted to explore further indications and novel drugs related to DLL3-targeting antibodies. IDH-mutant gliomas show selective and homogeneous expression of DLL3, and researchers found that patient-derived IDH-mutant glioma tumorspheres were sensitive to Rova-T in vitro⁵⁹⁰. Another DLL3 ADC, SC-002, presented an ORR of 14% and a severe AE rate of 37% in a phase I clinical trial in SCLC⁵⁹¹. Furthermore, some novel drugs targeting DLL3 are in trials actively recruiting patients, such as AM757 (a bispecific antibody targeting DLL3 and CD3, NCT04702737) and HPN328 (a trispecific antibody, NCT04471727).

DLL4

DLL4 is an important regulator of tumor angiogenesis and cancer stem cells and is activated in a wide range of human cancers⁵⁹². The combination of specific DLL4 blockade and ionizing radiation impairs tumor growth by promoting nonfunctional tumor angiogenesis and extensive tumor necrosis⁵⁹³. When combined with VEGF blockade, REGN421, a monoclonal antibody targeting DLL4, presented antitumor effects in ovarian cancer⁵²⁵. A phase I clinical trial of REGN421, also called enoticumab, was conducted in patients with advanced solid tumors. Of the 32 treated patients in whom toxicity was tolerable, 2 patients had partial response, and 16 patients had stable disease⁵⁹⁴. Demcizumab, another anti-DLL4 antibody, showed antitumor activity at the minimum dose and with shorter exposure in a phase I clinical study of solid tumors but presented a significant risk of cardiac toxicity⁵⁹⁵. After dose optimization, combining demcizumab with paclitaxel achieved an ORR of 21% in platinum-resistant ovarian cancer patients without dose-limiting toxicity⁵⁹⁶. Strategies employing dual variable domain immunoglobulin (DVD-Ig) molecules targeting DLL4 and VEGF have been studied, such as ABT-165, which showed superior efficacy and safety in preclinical models⁵⁹⁷, and navicixizumab (OMP-305B83), which presented modest antitumor potency and toxicity in a phase Ib clinical trial of solid tumors⁵⁹⁸.

JAG2/DLL1

JAG2, believed to promote cell survival and proliferation, interacts with NOTCH2, the nucleus pulposus (NP)⁵⁹⁹, and hematopoietic stem and progenitor cells (HSPCs)⁶⁰⁰. Additionally, high expression of JAG2 facilitates the development of cancers, such as lung adenocarcinoma⁶⁰¹ and bladder cancer⁶⁰². DLL1 is essential for the development and differentiation of B lymphocytes^227,603. These two ligands might be promising targets, although drugs targeting these ligands have yet to be reported.

Antibodies against receptors

NOTCH1

Mutant NOTCH1 induces the occurrence of T-ALL and T-ALL cell proliferation^344,604. It can also act as an oncogene in colorectal carcinoma⁶⁰⁵, glioma⁶⁰⁶ and other malignant tumors⁶⁰⁷, making it a possible antitumor target. In phase I clinical trials, a monoclonal antibody targeting NOTCH1 called brontictuzumab was tested in patients with solid tumors (NCT03031691 and NCT01778439) and lymphoid malignancies (NCT01703572). A clinical benefit was achieved in 6 of 12 ACC patients with tolerable toxicity⁴²⁰. In addition to tumor activation, NOTCH1 also promotes the immune response depending on Tregs. In preclinical trials, drugs selectively inhibiting NOTCH1 have been shown to strengthen the function of Tregs to suppress the progression of inflammatory arthritis⁶⁰⁸ and modulate the immune response in transplantation⁶⁰⁹.

NOTCH2/NOTCH3

Dysregulated NOTCH2 is vital for the development of cancers such as some B cell leukemias⁶¹⁰, pancreatic ductal adenocarcinoma (PDAC)⁶¹¹, and malignant melanoma⁶¹². Similarly, NOTCH3 acts as a facilitating factor in various tumors, such as lung cancer⁶¹³, ERBB2-negative breast cancer⁶¹⁴, and ovarian cancer³⁹¹. OMP-59R5 (tarextumab), which blocks both NOTCH2 and NOTCH3, is effective in treating a variety of tumors³⁹⁷ and has been tested as a treatment for PDAC⁶¹⁵, SCLC (NCT01859741), and other solid tumors⁶¹⁶ in clinical trials. However, OMP-59R5 in combination with chemotherapy did not produce a superior outcome in PDAC or SCLC patients, and neither drug achieved a better objective response in other solid tumors. PF-06650808, a novel anti-NOTCH3 ADC, achieved 5 partial responses among 40 patients with breast cancer or other solid tumors, with a manageable safety profile and positive NOTCH3 expression detected in all responders⁶¹⁷.

NOTCH4

The functions of NOTCH4 differ in different types of cancer. The overexpression of NOTCH4 is regarded as a poor prognosis marker in some scenarios⁶¹⁸, while in others, it is considered a favorable marker⁶¹⁹. There are no mature drugs targeting NOTCH4.

Transcription blockers

Activating the transcription of target genes is the last step of NOTCH signaling. Therapies targeting downstream mediators of NOTCH signaling remain unexplored. NOTCH transcription depends on the NOTCH ternary complex (NTC), which contains the DNA-binding protein CSL (also called CBF-1/RBPJ, Su (H), or Lag-1), NICD and MAML1^620,621. RIN1, a small molecule inhibitor of RBPJ, causes proliferation of hematologic cancer cell lines in vitro⁶²². IMR-1, a small molecule inhibitor of MAML1, inhibits the growth of NOTCH-dependent cell lines in vitro⁶²³. CB-103, an orally active small molecule altering NTC function, produces loss-of-function NOTCH phenotypes and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity of other NOTCH inhibitors⁶²⁴. Such novel drugs may represent new agents for NOTCH-based diseases.

NOTCH signaling agonists

NOTCH signaling can both accelerate and suppress the development of diseases, which unsurprisingly applies in cancers^625,626. That is, enhancing NOTCH signaling can be a targeted therapy strategy. Some chrysin and hesperetin compounds have been used to activate NOTCH signaling in anaplastic thyroid cancer with NOTCH1 deficiency^627,628. Inhibitory effects on established tumor cell lines were found, although the underlying mechanism remains unclear. The negative regulatory region (NRR) can autoinhibit the metalloprotease cleavage of NOTCH to enhance its signaling. Some activating antibodies of NOTCH receptors induce conformational changes in the NRR, making it accessible to ADAM metalloproteinases, thus facilitating activation of NOTCH signaling⁶²⁹.

Summary of clinical trials

Several NOTCH-targeted therapies have been evaluated in clinical trials; specifically, these therapies have been tested in cancers⁴¹. Among cleavage inhibitors, drugs targeting S1-S2 cleavage are still within preclinical stages. Drugs targeting S3 cleavage (GSIs and GSMs) have made their way into further clinical research; research of GSIs has been restrained due to severe toxicities, though GSMs are being continuously explored. Among the antibodies against ligands, drugs targeting JAG1, DLL3 and DLL4 have shown promising results in preclinical studies. Drugs targeting DLL3 and DLL4 have been studied in early clinical trials, with only those targeting DLL3 performing well. Unfortunately, further studies of agents targeting DLL3 failed to meet expectations. Drugs targeting JAG2/DLL1 have shown great potential, but no drug has reached mature development. Among the antibodies against receptors, the majority have achieved mediocre results. Of the transcription blockers and signal agonists, the blockers have only been studied in the preclinical stage, while agonists remain only theoretical. Of the abovementioned agents, those targeting DLL3 and GSIs are the most popular because they have shown potential.

However, neither of these agents can be applied clinically considering safety and efficacy. On the one hand, most pan-NOTCH inhibitors exhibit dose-limiting gastrointestinal toxicities mediated by hyperplasia of intestinal goblet cells, including diarrhea and vomiting, which often lead to suspension of further investigations^253,630. Regarding GSIs, attempts have been made to improve tolerance, such as combining GSIs with glucocorticoids⁶³¹, using intermittent dosing regimens⁶³², and applying drugs that inhibit disease-specific subunits of the γ-secretase complex⁶³³. On the other hand, the majority of ADCs have failed to reach the expected efficacy in cancer studies, although they have performed well in some individuals. Cell heterogeneity might be an explanation for such findings. Taking SCLC as an example, researchers found that a minority of nonneuroendocrine SCLC cells with NOTCH activation could sustain the growth of neuroendocrine SCLC cells without NOTCH activation and exhibit cancer stem cell-like properties⁶³⁴, resulting in primary resistance to anti-DLL3 drugs. Insufficient affinity of ADCs might be another reasonable explanation. Additionally, the complexity of NOTCH signaling and bypass signaling might circumvent NOTCH-targeted therapies. In the future, exploring predictive biomarkers, reducing drug toxicities, and exploiting multitargeted drugs might overcome the challenges of NOTCH-targeted therapies.

Concluding remarks and future perspectives

It has been approximately 110 years since the NOTCH gene was first identified in D. melanogaster. We summarized both classical and cutting-edge findings of NOTCH signaling in this review, illustrating the history, architecture, regulatory mechanism, physiology, and pathology of NOTCH signaling as well as therapeutics targeting NOTCH signaling. We identified certain areas of basic research and clinical applications of NOTCH signaling as worthy of further exploration.

One of the most interesting things regarding NOTCH signaling is the dual role it plays in different conditions, particularly in cancers. First, the functions of NOTCH signaling are different within the same tissues, and this is possibly caused by the utilization of different ligands; for example, DLL4/JAG1 regulates tumor vasculature, and DLL1/JAG2 regulate DC functions. Second, the functions of NOTCH signaling vary in different tissues. For instance, NOTCH acts as an oncogene in some tumors and as a tumor suppressor gene in others. Several mechanisms might explain this phenomenon: (a) Different tissues have different expression patterns of NOTCH signaling components, and thus, the outcomes of NOTCH signaling are tissue-specific; for example, DLL3 has tissue-specific effects in SCLC, and NOTCH1 has tissue-specific effects in T-ALL. (b) NOTCH signaling effects occur over a small range, while the cell morphology and intercellular distance are diverse in different tissues. (c) NOTCH signaling activates the transcription of a series of genes containing both positive and negative regulators of biological events. As these downstream genes are also regulated by other driver genes, such as Myc and P53, the mutational status of these driver genes also affects the outcome of NOTCH signaling. Third, tumors are massive complexes containing different clones of cancer cells and multiple types of noncancerous cells, making the overall effect of NOTCH signaling complicated and unpredictable.

Several strategies can be employed to clarify the mechanisms of NOTCH signaling. First, deciphering the subtle differences between different ligand–receptor interactions is essential. Second, spatially resolved transcriptomic analyses⁶³⁵, which dissect the embedded tissues into very small pieces and acquire their expression profiles, can be used to explore the impact of spatial characteristics on the outcome of NOTCH signaling. Third, comprehensive analysis of NOTCH target genes is needed because there may be more target genes than are currently known⁸¹, and epigenetic and transcriptomic analyses might help.

NOTCH-targeted therapy has been studied for decades but has failed to meet expectations. The reasons for these shortcomings might be the cytotoxicity induced by pan-NOTCH inhibitors, the low affinity of current ADCs, and the upregulation of bypass pathways. Novel drugs such as isoform-specific drugs and high-affinity ADCs may be a solution, as they might have increased efficacy and lower cytotoxicity. In addition, protein refolding is an attractive mode of action to employ to restore the functions of inactivated NOTCH signaling. Another strategy is to develop novel treatment strategies, such as DC-pulsed vaccine therapy and synNOTCH CAR-T cell therapy. Complementary combination therapies, such as combination of inhibitors of other pathways, chemotherapy, radiation therapy, and immunotherapy, are also promising. Among these potential combinations, combinations with immunotherapy are expected to be the most useful.

Much work remains to be accomplished for combining NOTCH-targeted therapy with immunotherapy, and the following strategies might help. First, functional studies are needed to comprehensively delineate the consequences of different NOTCH mutations and their effects on the immune microenvironment. NOTCH plays a complex role in tumor immunity, and its overall impact on tumors remains unclear. Second, clinical applications targeting different stages and types of cancer should be considered separately. Canonical NOTCH signaling is widely activated among cells to mediate adjacent intercellular interactions, yet its effects are highly dependent on context and/or cancer type. Third, appropriate ligands and/or receptors should be well chosen because they may have contradictory biological effects. For example, DLL1-NOTCH mainly functions as an immune-activating signal in DCs and CD8+ T cells. However, JAG1/2-NOTCH mainly functions as an immunosuppressive signal, inhibiting DCs and CD8+ T cells while activating many immunosuppressive cells. It is evident that drugs selectively enhancing DLL1-NOTCH signaling while inhibiting JAG1/2-NOTCH signaling can outperform pan-NOTCH-targeting drugs in actual practice. Fourth, conditions triggering the anti-immune or proimmune effects of NOTCH signaling in tumor cells should be considered. It has been acknowledged that NOTCH signaling may be immunosuppressive or tumor suppressive, yet the conditions or triggering factors leading to certain effects remain unknown. Thus, the effect of NOTCH signaling under different microenvironments should be investigated to generate better and more predictable medical applications. Fifth, cytotoxicity should be considered, including the toxicity of the drug itself and the toxicities induced by combination therapies. Sixth, predictive biomarkers should be explored to bolster NOTCH-targeting monotherapy and/or ICI therapy should be combined with NOTCH-targeting monotherapy to achieve maximum efficacy.

In summary, NOTCH factors present complicated and highly changeable functions, suggesting that elaboration of the general mechanism is required. Novel drugs with higher efficacy and lower cytotoxicity are worth investigating, as are new therapeutic strategies. Once a complete understanding of NOTCH signaling is achieved, it can be applied in actual medical practice, fulfilling the long-overdue mission of benefiting patients.

References

Metz, C. W. & Bridges, C. B. Incompatibility of mutant races in Drosophila. Proc. Natl Acad. Sci. USA 3, 673–678 (1917).
Article CAS PubMed PubMed Central Google Scholar
Mohr, O. L. Character changes caused by mutation of an entire region of a chromosome in Drosophila. Genetics 4, 275–282 (1919).
Article CAS PubMed PubMed Central Google Scholar
Bridges, C. B. Non-disjunction as proof of the chromosome theory of heredity (concluded). Genetics 1, 107–163 (1916).
Article CAS PubMed PubMed Central Google Scholar
Yochem, J., Weston, K. & Greenwald, I. The Caenorhabditis elegans lin-12 gene encodes a transmembrane protein with overall similarity to Drosophila Notch. Nature 335, 547–550 (1988).
Article CAS PubMed Google Scholar
Austin, J. & Kimble, J. Transcript analysis of glp-1 and lin-12, homologous genes required for cell interactions during development of C. elegans. Cell 58, 565–571 (1989).
Article CAS PubMed Google Scholar
Coffman, C., Harris, W. & Kintner, C. Xotch, the Xenopus homolog of Drosophila notch. Science 249, 1438–1441 (1990).
Article CAS PubMed Google Scholar
Stubbs, J. D. et al. cDNA cloning of a mouse mammary epithelial cell surface protein reveals the existence of epidermal growth factor-like domains linked to factor VIII-like sequences. Proc. Natl Acad. Sci. USA 87, 8417–8421 (1990).
Article CAS PubMed PubMed Central Google Scholar
Lodewijk, G. A., Fernandes, D. P., Vretzakis, I., Savage, J. E. & Jacobs, F. M. J. Evolution of human brain size-associated NOTCH2NL genes proceeds toward reduced protein levels. Mol. Biol. Evol. 37, 2531–2548 (2020).
Article CAS PubMed PubMed Central Google Scholar
Artavanis-Tsakonas, S., Muskavitch, M. A. & Yedvobnick, B. Molecular cloning of Notch, a locus affecting neurogenesis in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 80, 1977–1981 (1983).
Article CAS PubMed PubMed Central Google Scholar
Wharton, K. A., Johansen, K. M., Xu, T. & Artavanis-Tsakonas, S. Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 43, 567–581 (1985).
Article CAS PubMed Google Scholar
Kidd, S., Kelley, M. R. & Young, M. W. Sequence of the notch locus of Drosophila melanogaster: relationship of the encoded protein to mammalian clotting and growth factors. Mol. Cell Biol. 6, 3094–3108 (1986).
CAS PubMed PubMed Central Google Scholar
Johansen, K. M., Fehon, R. G. & Artavanis-Tsakonas, S. The notch gene product is a glycoprotein expressed on the cell surface of both epidermal and neuronal precursor cells during Drosophila development. J. Cell Biol. 109, 2427–2440 (1989).
Article CAS PubMed Google Scholar
Rykowski, M. C., Parmelee, S. J., Agard, D. A. & Sedat, J. W. Precise determination of the molecular limits of a polytene chromosome band: regulatory sequences for the Notch gene are in the interband. Cell 54, 461–472 (1988).
Article CAS PubMed Google Scholar
Cagan, R. L. & Ready, D. F. Notch is required for successive cell decisions in the developing Drosophila retina. Genes Dev. 3, 1099–1112 (1989).
Article CAS PubMed Google Scholar
Xu, T., Rebay, I., Fleming, R. J., Scottgale, T. N. & Artavanis-Tsakonas, S. The Notch locus and the genetic circuitry involved in early Drosophila neurogenesis. Genes Dev. 4, 464–475 (1990).
Article CAS PubMed Google Scholar
Hartley, D. A., Xu, T. A. & Artavanis-Tsakonas, S. The embryonic expression of the Notch locus of Drosophila melanogaster and the implications of point mutations in the extracellular EGF-like domain of the predicted protein. EMBO J. 6, 3407–3417 (1987).
Article CAS PubMed PubMed Central Google Scholar
Breeden, L. & Nasmyth, K. Similarity between cell-cycle genes of budding yeast and fission yeast and the Notch gene of Drosophila. Nature 329, 651–654 (1987).
Article CAS PubMed Google Scholar
Kidd, S. & Young, M. W. Transposon-dependent mutant phenotypes at the Notch locus of Drosophila. Nature 323, 89–91 (1986).
Article CAS PubMed Google Scholar
Austin, J. & Kimble, J. glp-1 is required in the germ line for regulation of the decision between mitosis and meiosis in C. elegans. Cell 51, 589–599 (1987).
Article CAS PubMed Google Scholar
Greenwald, I. S., Sternberg, P. W. & Horvitz, H. R. The lin-12 locus specifies cell fates in Caenorhabditis elegans. Cell 34, 435–444 (1983).
Article CAS PubMed Google Scholar
Kopan, R. & Ilagan, M. X. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137, 216–233 (2009).
Article CAS PubMed PubMed Central Google Scholar
Gazave, E. et al. Origin and evolution of the notch signalling pathway: an overview from eukaryotic genomes. BMC Evol. Biol. 9, 249 (2009).
Article PubMed PubMed Central CAS Google Scholar
Käsbauer, T. et al. The Notch signaling pathway in the cnidarian Hydra. Dev. Biol. 303, 376–390 (2007).
Article PubMed CAS Google Scholar
Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signaling: cell fate control and signal integration in development. Science 284, 770–776 (1999).
Article CAS PubMed Google Scholar
Fernández, R. & Gabaldón, T. Gene gain and loss across the metazoan tree of life. Nat. Ecol. Evol. 4, 524–533 (2020).
Article PubMed PubMed Central Google Scholar
Cary, G. A. et al. Systematic comparison of sea urchin and sea star developmental gene regulatory networks explains how novelty is incorporated in early development. Nat. Commun. 11, 6235 (2020).
Article CAS PubMed PubMed Central Google Scholar
Li, L. et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat. Genet. 16, 243–251 (1997).
Article CAS PubMed Google Scholar
Oda, T. et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat. Genet. 16, 235–242 (1997).
Article CAS PubMed Google Scholar
Deangelo, D. J. et al. A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias. J. Clin. Oncol. 24, 6585–6585 (2006).
Article Google Scholar
Andersson, E. R. & Lendahl, U. Therapeutic modulation of Notch signalling-are we there yet? Nat. Rev. Drug Discov. 13, 357–378 (2014).
Article CAS PubMed Google Scholar
Yang, G. et al. Structural basis of Notch recognition by human γ-secretase. Nature 565, 192–197 (2019).
Article CAS PubMed Google Scholar
Zhou, R. et al. Recognition of the amyloid precursor protein by human γ-secretase. Science 363, eaaw0930 (2019).
Yang, G. et al. Structural basis of γ-secretase inhibition and modulation by small molecule drugs. Cell 184, 521–533.e514 (2021).
Article CAS PubMed Google Scholar
Sarin, A. & Marcel, N. The NOTCH1-autophagy interaction: regulating self-eating for survival. Autophagy 13, 446–447 (2017).
Article CAS PubMed Google Scholar
Polacheck, W. J. et al. A non-canonical Notch complex regulates adherens junctions and vascular barrier function. Nature 552, 258–262 (2017).
Article CAS PubMed PubMed Central Google Scholar
Li, L. et al. Aberrant activation of notch1 signaling in glomerular endothelium induces albuminuria. Circ. Res 128, 602–618 (2021).
Article CAS PubMed Google Scholar
Horita, N. et al. Delta-like 1-expressing cells at the gland base promote proliferation of gastric antral stem cells in mouse. Cell Mol. Gastroenterol. Hepatol. 13, 275–287 (2021).
Article PubMed PubMed Central Google Scholar
Chang, D. & Shain, A. H. The landscape of driver mutations in cutaneous squamous cell carcinoma. NPJ Genom. Med. 6, 61 (2021).
Article CAS PubMed PubMed Central Google Scholar
Dorsam, R. T. & Gutkind, J. S. G-protein-coupled receptors and cancer. Nat. Rev. Cancer 7, 79–94 (2007).
Article CAS PubMed Google Scholar
Lemmon, M. A. & Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 141, 1117–1134 (2010).
Article CAS PubMed PubMed Central Google Scholar
Majumder, S. et al. Targeting Notch in oncology: the path forward. Nat. Rev. Drug Discov. 20, 125–144 (2021).
Article CAS PubMed Google Scholar
Siebel, C. & Lendahl, U. Notch signaling in development, tissue homeostasis, and disease. Physiol. Rev. 97, 1235–1294 (2017).
Article CAS PubMed Google Scholar
Kovall, R. A., Gebelein, B., Sprinzak, D. & Kopan, R. The canonical notch signaling pathway: structural and biochemical insights into shape, sugar, and force. Dev. Cell 41, 228–241 (2017).
Article CAS PubMed PubMed Central Google Scholar
Lee, T. V. et al. Negative regulation of notch signaling by xylose. PLoS Genet. 9, e1003547 (2013).
Article CAS PubMed PubMed Central Google Scholar
Sethi, M. K. et al. Identification of glycosyltransferase 8 family members as xylosyltransferases acting on O-glucosylated notch epidermal growth factor repeats. J. Biol. Chem. 285, 1582–1586 (2010).
Article CAS PubMed Google Scholar
Sethi, M. K. et al. Molecular cloning of a xylosyltransferase that transfers the second xylose to O-glucosylated epidermal growth factor repeats of notch. J. Biol. Chem. 287, 2739–2748 (2012).
Article CAS PubMed Google Scholar
Shi, S. & Stanley, P. Protein O-fucosyltransferase 1 is an essential component of Notch signaling pathways. Proc. Natl Acad. Sci. USA 100, 5234–5239 (2003).
Article CAS PubMed PubMed Central Google Scholar
Sasamura, T. et al. neurotic, a novel maternal neurogenic gene, encodes an O-fucosyltransferase that is essential for Notch-Delta interactions. Development 130, 4785–4795 (2003).
Article CAS PubMed Google Scholar
Moloney, D. J. et al. Fringe is a glycosyltransferase that modifies Notch. Nature 406, 369–375 (2000).
Article CAS PubMed Google Scholar
Wang, Y. et al. Fucosylation deficiency in mice leads to colitis and adenocarcinoma. Gastroenterology 152, 193–205.e10 (2017).
Article CAS PubMed Google Scholar
Servián-Morilla, E. et al. POGLUT1 biallelic mutations cause myopathy with reduced satellite cells, α-dystroglycan hypoglycosylation and a distinctive radiological pattern. Acta Neuropathol. 139, 565–582 (2020).
Article PubMed PubMed Central CAS Google Scholar
Zeronian, M. R. et al. Notch-Jagged signaling complex defined by an interaction mosaic. Proc Natl Acad Sci USA 118, e2102502118 (2021).
Yuan, X. et al. Notch signaling: an emerging therapeutic target for cancer treatment. Cancer Lett. 369, 20–27 (2015).
Article CAS PubMed Google Scholar
Capaccione, K. M. & Pine, S. R. The Notch signaling pathway as a mediator of tumor survival. Carcinogenesis 34, 1420–1430 (2013).
Article CAS PubMed PubMed Central Google Scholar
Owen, D. H. et al. DLL3: an emerging target in small cell lung cancer. J. Hematol. Oncol. 12, 61 (2019).
Article PubMed PubMed Central Google Scholar
Pitulescu, M. E. et al. Dll4 and Notch signalling couples sprouting angiogenesis and artery formation. Nat. Cell Biol. 19, 915–927 (2017).
Article CAS PubMed Google Scholar
Langridge, P. D. & Struhl, G. Epsin-dependent ligand endocytosis activates notch by force. Cell 171, 1383–1396.E12 (2017).
Article CAS PubMed PubMed Central Google Scholar
Gordon, W. R. et al. Structural basis for autoinhibition of Notch. Nat. Struct. Mol. Biol. 14, 295–300 (2007).
Article CAS PubMed Google Scholar
Stephenson, N. L. & Avis, J. M. Direct observation of proteolytic cleavage at the S2 site upon forced unfolding of the Notch negative regulatory region. Proc. Natl Acad. Sci. USA 109, E2757–2765 (2012).
Article CAS PubMed PubMed Central Google Scholar
Gordon, W. R. et al. Mechanical allostery: evidence for a force requirement in the proteolytic activation of notch. Dev. Cell 33, 729–736 (2015).
Article CAS PubMed PubMed Central Google Scholar
Xu, X. et al. Insights into autoregulation of Notch3 from structural and functional studies of its negative regulatory region. Structure 23, 1227–1235 (2015).
Article CAS PubMed PubMed Central Google Scholar
Seegar, T. C. M. et al. Structural basis for regulated proteolysis by the α-secretase ADAM10. Cell 171, 1638–1648.e1637 (2017).
Article CAS PubMed PubMed Central Google Scholar
Lambrecht, B. N., Vanderkerken, M. & Hammad, H. The emerging role of ADAM metalloproteinases in immunity. Nat. Rev. Immunol. 18, 745–758 (2018).
Article CAS PubMed Google Scholar
Du, H. et al. Macrophage-released ADAMTS1 promotes muscle stem cell activation. Nat. Commun. 8, 669 (2017).
Article PubMed PubMed Central CAS Google Scholar
Groot, A. J. & Vooijs, M. A. The role of Adams in Notch signaling. Adv. Exp. Med. Biol. 727, 15–36 (2012).
Article CAS PubMed PubMed Central Google Scholar
Li, Y. M. et al. Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature 405, 689–694 (2000).
Article CAS PubMed Google Scholar
Li, Y. M. et al. Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state. Proc. Natl Acad. Sci. USA 97, 6138–6143 (2000).
Article CAS PubMed PubMed Central Google Scholar
Kimberly, W. T. et al. Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc. Natl Acad. Sci. USA 100, 6382–6387 (2003).
Article CAS PubMed PubMed Central Google Scholar
Golde, T. E., Estus, S., Younkin, L. H., Selkoe, D. J. & Younkin, S. G. Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 255, 728–730 (1992).
Article CAS PubMed Google Scholar
Takami, M. et al. gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J. Neurosci. 29, 13042–13052 (2009).
Article CAS PubMed PubMed Central Google Scholar
Suzuki, N. et al. An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 264, 1336–1340 (1994).
Article CAS PubMed Google Scholar
Hardy, J. A. & Higgins, G. A. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).
Article CAS PubMed Google Scholar
Deatherage, C. L. et al. Structural and biochemical differences between the Notch and the amyloid precursor protein transmembrane domains. Sci. Adv. 3, e1602794 (2017).
Article PubMed PubMed Central CAS Google Scholar
Conner, S. D. Regulation of notch signaling through intracellular transport. Int Rev. Cell Mol. Biol. 323, 107–127 (2016).
Article CAS PubMed Google Scholar
Huenniger, K. et al. Notch1 signaling is mediated by importins alpha 3, 4, and 7. Cell Mol. Life Sci. 67, 3187–3196 (2010).
Article CAS PubMed PubMed Central Google Scholar
Bottoni, G. et al. CSL controls telomere maintenance and genome stability in human dermal fibroblasts. Nat. Commun. 10, 3884 (2019).
Article PubMed PubMed Central CAS Google Scholar
Dreval, K., Lake, R. J. & Fan, H.-Y. HDAC1 negatively regulates selective mitotic chromatin binding of the Notch effector RBPJ in a KDM5A-dependent manner. Nucleic Acids Res. 47, 4521–4538 (2019).
Article CAS PubMed PubMed Central Google Scholar
Aster, J. C., Pear, W. S. & Blacklow, S. C. The varied roles of notch in cancer. Annu Rev. Pathol. 12, 245–275 (2017).
Article CAS PubMed Google Scholar
Bray, S. J. Notch signalling in context. Nat. Rev. Mol. Cell Biol. 17, 722–735 (2016).
Article CAS PubMed Google Scholar
Lee, C., Sorensen, E. B., Lynch, T. R. & Kimble, J. C. elegans GLP-1/Notch activates transcription in a probability gradient across the germline stem cell pool. Elife 5, e18370 (2016).
Gomez-Lamarca, M. J. et al. Activation of the notch signaling pathway in vivo elicits changes in CSL nuclear dynamics. Dev. Cell 44, 611–623.e617 (2018).
Article CAS PubMed PubMed Central Google Scholar
Pillidge, Z. & Bray, S. J. SWI/SNF chromatin remodeling controls Notch-responsive enhancer accessibility. EMBO Rep. 20, e46944 (2019).
Lee, C., Shin, H. & Kimble, J. Dynamics of notch-dependent transcriptional bursting in its native context. Dev. Cell 50, 426–435.e4 (2019).
Article CAS PubMed PubMed Central Google Scholar
Petrovic, J. et al. Oncogenic notch promotes long-range regulatory interactions within hyperconnected 3D cliques. Mol. Cell 73, 1174–1190 (2019).
Article CAS PubMed PubMed Central Google Scholar
Pamarthy, S., Kulshrestha, A., Katara, G. K. & Beaman, K. D. The curious case of vacuolar ATPase: regulation of signaling pathways. Mol. Cancer 17, 41 (2018).
Article PubMed PubMed Central CAS Google Scholar
Jin, K. et al. NOTCH-induced rerouting of endosomal trafficking disables regulatory T cells in vasculitis. J. Clin. Invest. 131, e136042 (2021).
Steinbuck, M. P., Arakcheeva, K. & Winandy, S. Novel TCR-mediated mechanisms of notch activation and signaling. J. Immunol. 200, 997–1007 (2018).
Article CAS PubMed Google Scholar
Radtke, F., MacDonald, H. R. & Tacchini-Cottier, F. Regulation of innate and adaptive immunity by Notch. Nat. Rev. Immunol. 13, 427–437 (2013).
Article CAS PubMed Google Scholar
Song, L. L. et al. Notch-1 associates with IKKalpha and regulates IKK activity in cervical cancer cells. Oncogene 27, 5833–5844 (2008).
Article CAS PubMed Google Scholar
Yue, F. et al. Pten is necessary for the quiescence and maintenance of adult muscle stem cells. Nat. Commun. 8, 14328 (2017).
Article CAS PubMed PubMed Central Google Scholar
Chen, L.-J. et al. Gm364 coordinates MIB2/DLL3/Notch2 to regulate female fertility through AKT activation. Cell Death Differ (2021).
Li, H. et al. NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent manner. J. Exp. Clin. Cancer Res. 39, 128 (2020).
Article PubMed PubMed Central CAS Google Scholar
Mangolini, M. et al. Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia. Nat. Commun. 9, 3839 (2018).
Article PubMed PubMed Central CAS Google Scholar
Rajakulendran, N. et al. Wnt and Notch signaling govern self-renewal and differentiation in a subset of human glioblastoma stem cells. Genes Dev. 33, 498–510 (2019).
Article CAS PubMed PubMed Central Google Scholar
Hammad, H. & Lambrecht, B. N. Wnt and Hippo pathways in regulatory T cells: a NOTCH above in asthma. Nat. Immunol. 21, 1313–1314 (2020).
Article CAS PubMed PubMed Central Google Scholar
Luo, K. Signaling cross talk between TGF-β/Smad and other signaling pathways. Cold Spring Harb. Perspect. Biol. 9, a022137 (2017).
Fernández-Majada, V. et al. Nuclear IKK activity leads to dysregulated notch-dependent gene expression in colorectal cancer. Proc. Natl Acad. Sci. USA 104, 276–281 (2007).
Article PubMed Google Scholar
Hossain, F. et al. Notch signaling regulates mitochondrial metabolism and NF-κB Activity in triple-negative breast cancer cells via IKKα-dependent non-canonical pathways. Front. Oncol. 8, 575 (2018).
Article PubMed PubMed Central Google Scholar
Kuramoto, T. et al. Dll4-Fc, an inhibitor of Dll4-notch signaling, suppresses liver metastasis of small cell lung cancer cells through the downregulation of the NF-κB activity. Mol. Cancer Ther. 11, 2578–2587 (2012).
Article CAS PubMed Google Scholar
Gentle, M. E., Rose, A., Bugeon, L. & Dallman, M. J. Noncanonical Notch signaling modulates cytokine responses of dendritic cells to inflammatory stimuli. J. Immunol. 189, 1274–1284 (2012).
Article CAS PubMed Google Scholar
Lin, S. et al. Non-canonical NOTCH3 signalling limits tumour angiogenesis. Nat. Commun. 8, 16074 (2017).
Article CAS PubMed PubMed Central Google Scholar
Pelullo, M. et al. Kras/ADAM17-dependent Jag1-ICD reverse signaling sustains colorectal cancer progression and chemoresistance. Cancer Res 79, 5575–5586 (2019).
Article CAS PubMed Google Scholar
Stahl, M. et al. Roles of Pofut1 and O-fucose in mammalian Notch signaling. J. Biol. Chem. 283, 13638–13651 (2008).
Article CAS PubMed PubMed Central Google Scholar
Yao, D. et al. Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions. Blood 117, 5652–5662 (2011).
Article CAS PubMed PubMed Central Google Scholar
Wang, Y. et al. Uncontrolled angiogenic precursor expansion causes coronary artery anomalies in mice lacking Pofut1. Nat. Commun. 8, 578 (2017).
Article PubMed PubMed Central CAS Google Scholar
Jafar-Nejad, H., Leonardi, J. & Fernandez-Valdivia, R. Role of glycans and glycosyltransferases in the regulation of Notch signaling. Glycobiology 20, 931–949 (2010).
Article CAS PubMed PubMed Central Google Scholar
Takeuchi, H. & Haltiwanger, R. S. Role of glycosylation of Notch in development. Semin. Cell Dev. Biol. 21, 638–645 (2010).
Article CAS PubMed PubMed Central Google Scholar
Luther, K. B. & Haltiwanger, R. S. Role of unusual O-glycans in intercellular signaling. Int. J. Biochem. Cell Biol. 41, 1011–1024 (2009).
Article CAS PubMed Google Scholar
Stanley, P. & Okajima, T. Roles of glycosylation in Notch signaling. Curr. Top. Dev. Biol. 92, 131–164 (2010).
Article CAS PubMed Google Scholar
Acar, M. et al. Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling. Cell 132, 247–258 (2008).
Article CAS PubMed PubMed Central Google Scholar
Fernandez-Valdivia, R. et al. Regulation of mammalian Notch signaling and embryonic development by the protein O-glucosyltransferase Rumi. Development 138, 1925–1934 (2011).
Article CAS PubMed PubMed Central Google Scholar
Ge, C. & Stanley, P. The O-fucose glycan in the ligand-binding domain of Notch1 regulates embryogenesis and T cell development. Proc. Natl Acad. Sci. USA 105, 1539–1544 (2008).
Article CAS PubMed PubMed Central Google Scholar
Rana, N. A. et al. O-glucose trisaccharide is present at high but variable stoichiometry at multiple sites on mouse Notch1. J. Biol. Chem. 286, 31623–31637 (2011).
Article CAS PubMed PubMed Central Google Scholar
Bousseau, S. et al. Glycosylation as new pharmacological strategies for diseases associated with excessive angiogenesis. Pharm. Ther. 191, 92–122 (2018).
Article CAS Google Scholar
Yeh, C.-H., Bellon, M. & Nicot, C. FBXW7: a critical tumor suppressor of human cancers. Mol. Cancer 17, 115 (2018).
Article PubMed PubMed Central CAS Google Scholar
Ye, L. et al. NUMB maintains bone mass by promoting degradation of PTEN and GLI1 via ubiquitination in osteoblasts. Bone Res. 6, 32 (2018).
Article PubMed PubMed Central CAS Google Scholar
Guo, Y. et al. Numb enriches a castration-resistant prostate cancer cell subpopulation associated with enhanced notch and hedgehog signaling. Clin. Cancer Res. 23, 6744–6756 (2017).
Article CAS PubMed Google Scholar
Liu, P., Verhaar, A. P. & Peppelenbosch, M. P. Signaling size: ankyrin and SOCS box-containing ASB E3 ligases in action. Trends Biochem. Sci. 44, 64–74 (2019).
Article CAS PubMed Google Scholar
Giebel, B. & Wodarz, A. Tumor suppressors: control of signaling by endocytosis. Curr. Biol. 16, R91–92 (2006).
Article CAS PubMed Google Scholar
Thompson, B. J. et al. Tumor suppressor properties of the ESCRT-II complex component Vps25 in Drosophila. Dev. Cell 9, 711–720 (2005).
Article CAS PubMed Google Scholar
Troost, T., Jaeckel, S., Ohlenhard, N. & Klein, T. The tumour suppressor Lethal (2) giant discs is required for the function of the ESCRT-III component Shrub/CHMP4. J. Cell Sci. 125, 763–776 (2012).
Article CAS PubMed Google Scholar
Vaccari, T. & Bilder, D. The Drosophila tumor suppressor vps25 prevents nonautonomous overproliferation by regulating notch trafficking. Dev. Cell 9, 687–698 (2005).
Article CAS PubMed Google Scholar
Chastagner, P., Israël, A. & Brou, C. Itch/AIP4 mediates Deltex degradation through the formation of K29-linked polyubiquitin chains. EMBO Rep. 7, 1147–1153 (2006).
Article CAS PubMed PubMed Central Google Scholar
Hori, K., Sen, A., Kirchhausen, T. & Artavanis-Tsakonas, S. Synergy between the ESCRT-III complex and Deltex defines a ligand-independent Notch signal. J. Cell Biol. 195, 1005–1015 (2011).
Article CAS PubMed PubMed Central Google Scholar
Shimizu, H. et al. Compensatory flux changes within an endocytic trafficking network maintain thermal robustness of Notch signaling. Cell 157, 1160–1174 (2014).
Article CAS PubMed PubMed Central Google Scholar
Wang, W. & Struhl, G. Distinct roles for Mind bomb, Neuralized and Epsin in mediating DSL endocytosis and signaling in Drosophila. Development 132, 2883–2894 (2005).
Article CAS PubMed Google Scholar
Overstreet, E., Fitch, E. & Fischer, J. A. Fat facets and Liquid facets promote Delta endocytosis and Delta signaling in the signaling cells. Development 131, 5355–5366 (2004).
Article CAS PubMed Google Scholar
Daskalaki, A. et al. Distinct intracellular motifs of Delta mediate its ubiquitylation and activation by Mindbomb1 and Neuralized. J. Cell Biol. 195, 1017–1031 (2011).
Article CAS PubMed PubMed Central Google Scholar
Le Borgne, R., Remaud, S., Hamel, S. & Schweisguth, F. Two distinct E3 ubiquitin ligases have complementary functions in the regulation of delta and serrate signaling in Drosophila. PLoS Biol. 3, e96 (2005).
Article PubMed PubMed Central Google Scholar
Fontana, J. R. & Posakony, J. W. Both inhibition and activation of Notch signaling rely on a conserved Neuralized-binding motif in Bearded proteins and the Notch ligand Delta. Dev. Biol. 333, 373–385 (2009).
Article CAS PubMed PubMed Central Google Scholar
Nandagopal, N., Santat, L. A. & Elowitz, M. B. activation in the Notch signaling pathway. eLife 8, e37880 (2019).
Chapman, G., Sparrow, D. B., Kremmer, E. & Dunwoodie, S. L. Notch inhibition by the ligand DELTA-LIKE 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. Hum. Mol. Genet. 20, 905–916 (2011).
Article CAS PubMed Google Scholar
Hoyne, G. F., Chapman, G., Sontani, Y., Pursglove, S. E. & Dunwoodie, S. L. A cell autonomous role for the Notch ligand Delta-like 3 in αβ T-cell development. Immunol. Cell Biol. 89, 696–705 (2011).
Article CAS PubMed Google Scholar
Kohlhaas, V. et al. Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1. Blood 137, 646–660 (2021).
Article CAS PubMed Google Scholar
Li, Y. et al. Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation. Blood 131, 191–201 (2018).
Article PubMed PubMed Central Google Scholar
Liu, M. et al. Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling. Nat. Commun. 8, 413 (2017).
Article PubMed PubMed Central CAS Google Scholar
Malik, N. et al. The transcription factor CBFB suppresses breast cancer through orchestrating translation and transcription. Nat. Commun. 10, 2071 (2019).
Article PubMed PubMed Central CAS Google Scholar
Gallo, C. et al. The bHLH transcription factor DEC1 promotes thyroid cancer aggressiveness by the interplay with NOTCH1. Cell Death Dis. 9, 871 (2018).
Article PubMed PubMed Central CAS Google Scholar
Chen, X. et al. MicroRNA-26a and −26b inhibit lens fibrosis and cataract by negatively regulating Jagged-1/Notch signaling pathway. Cell Death Differ. 24, 1990 (2017).
Article CAS PubMed PubMed Central Google Scholar
Qiao, J. et al. MicroRNA-153 improves the neurogenesis of neural stem cells and enhances the cognitive ability of aged mice through the notch signaling pathway. Cell Death Differ. 27, 808–825 (2020).
Article CAS PubMed Google Scholar
Spitschak, A., Meier, C., Kowtharapu, B., Engelmann, D. & Pützer, B. M. MiR-182 promotes cancer invasion by linking RET oncogene activated NF-κB to loss of the HES1/Notch1 regulatory circuit. Mol. Cancer 16, 24 (2017).
Article PubMed PubMed Central CAS Google Scholar
Wasson, C. W. et al. Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH. Ann. Rheum. Dis. 79, 507–517 (2020).
Article CAS PubMed Google Scholar
Wang, R. et al. iNOS promotes CD24CD133 liver cancer stem cell phenotype through a TACE/ADAM17-dependent Notch signaling pathway. Proc. Natl Acad. Sci. USA 115, E10127–E10136 (2018).
Article CAS PubMed PubMed Central Google Scholar
Majumdar, U. et al. Nitric oxide prevents aortic valve calcification by S-nitrosylation of USP9X to activate NOTCH signaling. Sci. Adv. 7, eabe3706 (2021).
Morrugares, R. et al. Phosphorylation-dependent regulation of the NOTCH1 intracellular domain by dual-specificity tyrosine-regulated kinase 2. Cell Mol. Life Sci. 77, 2621–2639 (2020).
Article CAS PubMed Google Scholar
Suckling, R. J. et al. Structural and functional dissection of the interplay between lipid and Notch binding by human Notch ligands. EMBO J. 36, 2204–2215 (2017).
Article CAS PubMed PubMed Central Google Scholar
Baonza, A. & Garcia-Bellido, A. Notch signaling directly controls cell proliferation in the Drosophila wing disc. Proc. Natl Acad. Sci. USA 97, 2609–2614 (2000).
Article CAS PubMed PubMed Central Google Scholar
Knust, E. & Campos-Ortega, J. A. The molecular genetics of early neurogenesis in Drosophila melanogaster. Bioessays 11, 95–100 (1989).
Article CAS PubMed Google Scholar
Dray, N. et al. Dynamic spatiotemporal coordination of neural stem cell fate decisions occurs through local feedback in the adult vertebrate brain. Cell Stem Cell 28, 1457–1472.e1412 (2021).
Article CAS PubMed PubMed Central Google Scholar
Hilton, M. J. et al. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat. Med. 14, 306–314 (2008).
Article CAS PubMed PubMed Central Google Scholar
Dong, Y. et al. RBPjkappa-dependent Notch signaling regulates mesenchymal progenitor cell proliferation and differentiation during skeletal development. Development 137, 1461–1471 (2010).
Article CAS PubMed PubMed Central Google Scholar
Zong, Y. et al. Notch signaling controls liver development by regulating biliary differentiation. Development 136, 1727–1739 (2009).
Article CAS PubMed PubMed Central Google Scholar
Sparks, E. E., Huppert, K. A., Brown, M. A., Washington, M. K. & Huppert, S. S. Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice. Hepatology 51, 1391–1400 (2010).
Article CAS PubMed Google Scholar
Alabi, R. O., Farber, G. & Blobel, C. P. Intriguing roles for endothelial ADAM10/Notch signaling in the development of organ-specific vascular beds. Physiol. Rev. 98, 2025–2061 (2018).
Article CAS PubMed PubMed Central Google Scholar
Herbert, S. P. & Stainier, D. Y. Molecular control of endothelial cell behaviour during blood vessel morphogenesis. Nat. Rev. Mol. Cell Biol. 12, 551–564 (2011).
Article CAS PubMed PubMed Central Google Scholar
Hellström, M. et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445, 776–780 (2007).
Article PubMed CAS Google Scholar
Jakobsson, L. et al. Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting. Nat. Cell Biol. 12, 943–953 (2010).
Article CAS PubMed Google Scholar
Minnis-Lyons, S. E. et al. Notch-IGF1 signaling during liver regeneration drives biliary epithelial cell expansion and inhibits hepatocyte differentiation. Sci. Signal 14, eabe3706 (2021).
Peel, A. D., Chipman, A. D. & Akam, M. Arthropod segmentation: beyond the Drosophila paradigm. Nat. Rev. Genet. 6, 905–916 (2005).
Article CAS PubMed Google Scholar
Dequéant, M. L. et al. A complex oscillating network of signaling genes underlies the mouse segmentation clock. Science 314, 1595–1598 (2006).
Article PubMed CAS Google Scholar
Diaz-Cuadros, M. et al. In vitro characterization of the human segmentation clock. Nature 580, 113–118 (2020).
Article CAS PubMed PubMed Central Google Scholar
Sonnen, K. F. et al. Modulation of phase shift between Wnt and Notch signaling oscillations controls mesoderm segmentation. Cell 172, (2018).
Lewis, J. Autoinhibition with transcriptional delay: a simple mechanism for the zebrafish somitogenesis oscillator. Curr. Biol. 13, 1398–1408 (2003).
Article CAS PubMed Google Scholar
Hubaud, A., Regev, I., Mahadevan, L. & Pourquié, O. Excitable dynamics and yap-dependent mechanical cues drive the segmentation clock. Cell 171, 668–682.e611 (2017).
Article CAS PubMed PubMed Central Google Scholar
Pourquié, O. Vertebrate somitogenesis. Annu. Rev. Cell Dev. Biol. 17, 311–350 (2001).
Article PubMed Google Scholar
Bessho, Y., Hirata, H., Masamizu, Y. & Kageyama, R. Periodic repression by the bHLH factor Hes7 is an essential mechanism for the somite segmentation clock. Genes Dev. 17, 1451–1456 (2003).
Article CAS PubMed PubMed Central Google Scholar
Dale, J. K. et al. Periodic notch inhibition by lunatic fringe underlies the chick segmentation clock. Nature 421, 275–278 (2003).
Article CAS PubMed Google Scholar
Cole, S. E., Levorse, J. M., Tilghman, S. M. & Vogt, T. F. Clock regulatory elements control cyclic expression of Lunatic fringe during somitogenesis. Dev. Cell 3, 75–84 (2002).
Article CAS PubMed Google Scholar
Hubaud, A. & Pourquié, O. Signalling dynamics in vertebrate segmentation. Nat. Rev. Mol. Cell Biol. 15, 709–721 (2014).
Article CAS PubMed Google Scholar
Yoshioka-Kobayashi, K. et al. Coupling delay controls synchronized oscillation in the segmentation clock. Nature 580, 119–123 (2020).
Article CAS PubMed Google Scholar
Jiang, Y. J. et al. Notch signalling and the synchronization of the somite segmentation clock. Nature 408, 475–479 (2000).
Article CAS PubMed Google Scholar
Zhang, N. & Gridley, T. Defects in somite formation in lunatic fringe-deficient mice. Nature 394, 374–377 (1998).
Article CAS PubMed Google Scholar
Okubo, Y. et al. Lfng regulates the synchronized oscillation of the mouse segmentation clock via trans-repression of Notch signalling. Nat. Commun. 3, 1141 (2012).
Article PubMed CAS Google Scholar
Mead, T. J. & Yutzey, K. E. Notch pathway regulation of chondrocyte differentiation and proliferation during appendicular and axial skeleton development. Proc. Natl Acad. Sci. USA 106, 14420–14425 (2009).
Article CAS PubMed PubMed Central Google Scholar
Akiyama, H., Chaboissier, M. C., Martin, J. F., Schedl, A. & de Crombrugghe, B. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev. 16, 2813–2828 (2002).
Article CAS PubMed PubMed Central Google Scholar
Tsingas, M. et al. Sox9 deletion causes severe intervertebral disc degeneration characterized by apoptosis, matrix remodeling, and compartment-specific transcriptomic changes. Matrix Biol. 94, 110–133 (2020).
Article CAS PubMed PubMed Central Google Scholar
Long, F. & Ornitz, D. M. Development of the endochondral skeleton. Cold Spring Harb. Perspect. Biol. 5, a008334 (2013).
Article PubMed PubMed Central CAS Google Scholar
Liu, C. F., Samsa, W. E., Zhou, G. & Lefebvre, V. Transcriptional control of chondrocyte specification and differentiation. Semin. Cell Dev. Biol. 62, 34–49 (2017).
Article CAS PubMed Google Scholar
Luo, Z. et al. Notch signaling in osteogenesis, osteoclastogenesis, and angiogenesis. Am. J. Pathol. 189, 1495–1500 (2019).
Article CAS PubMed PubMed Central Google Scholar
Yu, J. & Canalis, E. Notch and the regulation of osteoclast differentiation and function. Bone 138, 115474 (2020).
Article CAS PubMed PubMed Central Google Scholar
Hankenson, K. D., Gagne, K. & Shaughnessy, M. Extracellular signaling molecules to promote fracture healing and bone regeneration. Adv. Drug Deliv. Rev. 94, 3–12 (2015).
Article CAS PubMed Google Scholar
Wang, C. et al. Transient gamma-secretase inhibition accelerates and enhances fracture repair likely via Notch signaling modulation. Bone 73, 77–89 (2015).
Article PubMed CAS Google Scholar
High, F. A. & Epstein, J. A. The multifaceted role of Notch in cardiac development and disease. Nat. Rev. Genet. 9, 49–61 (2008).
Article CAS PubMed Google Scholar
Niessen, K. & Karsan, A. Notch signaling in cardiac development. Circ. Res 102, 1169–1181 (2008).
Article CAS PubMed Google Scholar
Luxán, G., D’Amato, G., MacGrogan, D. & de la Pompa, J. L. Endocardial Notch signaling in cardiac development and disease. Circ. Res. 118, e1–e18 (2016).
Article PubMed CAS Google Scholar
de la Pompa, J. L. & Epstein, J. A. Coordinating tissue interactions: Notch signaling in cardiac development and disease. Dev. Cell 22, 244–254 (2012).
Article PubMed PubMed Central CAS Google Scholar
Rutenberg, J. B. et al. Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors. Development 133, 4381–4390 (2006).
Article CAS PubMed Google Scholar
Papoutsi, T., Luna-Zurita, L., Prados, B., Zaffran, S. & de la Pompa, J. L. Bmp2 and Notch cooperate to pattern the embryonic endocardium. Development 145 (2018).
Luna-Zurita, L. et al. Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation. J. Clin. Invest. 120, 3493–3507 (2010).
Article CAS PubMed PubMed Central Google Scholar
Timmerman, L. A. et al. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 18, 99–115 (2004).
Article CAS PubMed PubMed Central Google Scholar
Chen, H. et al. BMP10 is essential for maintaining cardiac growth during murine cardiogenesis. Development 131, 2219–2231 (2004).
Article CAS PubMed Google Scholar
Grego-Bessa, J. et al. Notch signaling is essential for ventricular chamber development. Dev. Cell 12, 415–429 (2007).
Article CAS PubMed PubMed Central Google Scholar
Holderfield, M. T. & Hughes, C. C. Crosstalk between vascular endothelial growth factor, notch, and transforming growth factor-beta in vascular morphogenesis. Circ. Res. 102, 637–652 (2008).
Article CAS PubMed Google Scholar
Krebs, L. T. et al. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev. 14, 1343–1352 (2000).
Article CAS PubMed PubMed Central Google Scholar
Lobov, I. B. et al. Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc. Natl Acad. Sci. USA 104, 3219–3224 (2007).
Article CAS PubMed PubMed Central Google Scholar
Suchting, S. et al. The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc. Natl Acad. Sci. USA 104, 3225–3230 (2007).
Article CAS PubMed PubMed Central Google Scholar
Moldovan, G. E., Miele, L. & Fazleabas, A. T. Notch signaling in reproduction. Trends Endocrinol. Metab. 32, 1044–1057 (2021).
Article CAS PubMed Google Scholar
Zarkada, G., Heinolainen, K., Makinen, T., Kubota, Y. & Alitalo, K. VEGFR3 does not sustain retinal angiogenesis without VEGFR2. Proc. Natl Acad. Sci. USA 112, 761–766 (2015).
Article CAS PubMed PubMed Central Google Scholar
Hultgren, N. W. et al. Slug regulates the Dll4-Notch-VEGFR2 axis to control endothelial cell activation and angiogenesis. Nat. Commun. 11, 5400 (2020).
Article CAS PubMed PubMed Central Google Scholar
Phng, L. K. et al. Nrarp coordinates endothelial Notch and Wnt signaling to control vessel density in angiogenesis. Dev. Cell 16, 70–82 (2009).
Article CAS PubMed PubMed Central Google Scholar
Yang, J. M. et al. Dll4 suppresses transcytosis for arterial blood-retinal barrier homeostasis. Circ. Res. 126, 767–783 (2020).
Article CAS PubMed Google Scholar
High, F. A. et al. An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation. J. Clin. Invest 117, 353–363 (2007).
Article CAS PubMed PubMed Central Google Scholar
High, F. A. et al. Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proc. Natl Acad. Sci. USA 105, 1955–1959 (2008).
Article CAS PubMed PubMed Central Google Scholar
Boucher, J. M., Harrington, A., Rostama, B., Lindner, V. & Liaw, L. A receptor-specific function for Notch2 in mediating vascular smooth muscle cell growth arrest through cyclin-dependent kinase inhibitor 1B. Circ. Res. 113, 975–985 (2013).
Article CAS PubMed Google Scholar
Campos, A. H., Wang, W., Pollman, M. J. & Gibbons, G. H. Determinants of Notch-3 receptor expression and signaling in vascular smooth muscle cells: implications in cell-cycle regulation. Circ. Res. 91, 999–1006 (2002).
Article CAS PubMed Google Scholar
Baeten, J. T. & Lilly, B. Differential Regulation of NOTCH2 and NOTCH3 Contribute to Their Unique Functions in Vascular Smooth Muscle Cells. J. Biol. Chem. 290, 16226–16237 (2015).
Article CAS PubMed PubMed Central Google Scholar
Briot, A. et al. Repression of Sox9 by Jag1 is continuously required to suppress the default chondrogenic fate of vascular smooth muscle cells. Dev. Cell 31, 707–721 (2014).
Article CAS PubMed PubMed Central Google Scholar
Hasan, S. S. et al. Endothelial Notch signalling limits angiogenesis via control of artery formation. Nat. Cell Biol. 19, 928–940 (2017).
Article CAS PubMed PubMed Central Google Scholar
Luo, W. et al. Arterialization requires the timely suppression of cell growth. Nature 589, 437–441 (2021).
Article CAS PubMed Google Scholar
You, L. R. et al. Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature 435, 98–104 (2005).
Article CAS PubMed Google Scholar
Hainaud, P. et al. The role of the vascular endothelial growth factor-Delta-like 4 ligand/Notch4-ephrin B2 cascade in tumor vessel remodeling and endothelial cell functions. Cancer Res. 66, 8501–8510 (2006).
Article CAS PubMed Google Scholar
Fischer, A., Schumacher, N., Maier, M., Sendtner, M. & Gessler, M. The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev. 18, 901–911 (2004).
Article CAS PubMed PubMed Central Google Scholar
Pereira, F. A., Qiu, Y., Zhou, G., Tsai, M. J. & Tsai, S. Y. The orphan nuclear receptor COUP-TFII is required for angiogenesis and heart development. Genes Dev. 13, 1037–1049 (1999).
Article CAS PubMed PubMed Central Google Scholar
Corada, M., Morini, M. F. & Dejana, E. Signaling pathways in the specification of arteries and veins. Arterioscler Thromb. Vasc. Biol. 34, 2372–2377 (2014).
Article CAS PubMed Google Scholar
Trindade, A. et al. Overexpression of delta-like 4 induces arterialization and attenuates vessel formation in developing mouse embryos. Blood 112, 1720–1729 (2008).
Article CAS PubMed PubMed Central Google Scholar
Kume, T., Jiang, H., Topczewska, J. M. & Hogan, B. L. The murine winged helix transcription factors, Foxc1 and Foxc2, are both required for cardiovascular development and somitogenesis. Genes Dev. 15, 2470–2482 (2001).
Article CAS PubMed PubMed Central Google Scholar
Mack, J. J. et al. NOTCH1 is a mechanosensor in adult arteries. Nat. Commun. 8, 1620 (2017).
Article PubMed PubMed Central CAS Google Scholar
Weijts, B. et al. Blood flow-induced Notch activation and endothelial migration enable vascular remodeling in zebrafish embryos. Nat. Commun. 9, 5314 (2018).
Article CAS PubMed PubMed Central Google Scholar
Ditadi, A. et al. Human definitive haemogenic endothelium and arterial vascular endothelium represent distinct lineages. Nat. Cell Biol. 17, 580–591 (2015).
Article CAS PubMed PubMed Central Google Scholar
Butler, J. M. et al. Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. Cell Stem Cell 6, 251–264 (2010).
Article CAS PubMed PubMed Central Google Scholar
Wendorff, A. A. et al. Hes1 is a critical but context-dependent mediator of canonical Notch signaling in lymphocyte development and transformation. Immunity 33, 671–684 (2010).
Article CAS PubMed Google Scholar
Chen, E. L. Y., Thompson, P. K. & Zúñiga-Pflücker, J. C. RBPJ-dependent Notch signaling initiates the T cell program in a subset of thymus-seeding progenitors. Nat. Immunol. 20, 1456–1468 (2019).
Article CAS PubMed PubMed Central Google Scholar
Jenkinson, E. J., Jenkinson, W. E., Rossi, S. W. & Anderson, G. The thymus and T-cell commitment: the right niche for Notch? Nat. Rev. Immunol. 6, 551–555 (2006).
Article CAS PubMed Google Scholar
Yu, V. W. C. et al. Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow. J. Exp. Med. 212, 759–774 (2015).
Article CAS PubMed PubMed Central Google Scholar
Shah, N. J. et al. An injectable bone marrow-like scaffold enhances T cell immunity after hematopoietic stem cell transplantation. Nat. Biotechnol. 37, 293–302 (2019).
Article CAS PubMed PubMed Central Google Scholar
Shukla, S. et al. Progenitor T-cell differentiation from hematopoietic stem cells using Delta-like-4 and VCAM-1. Nat. Methods 14, 531–538 (2017).
Article CAS PubMed Google Scholar
Hozumi, K. et al. Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo. Nat. Immunol. 5, 638–644 (2004).
Article CAS PubMed Google Scholar
Descatoire, M. et al. Identification of a human splenic marginal zone B cell precursor with NOTCH2-dependent differentiation properties. J. Exp. Med. 211, (2014).
Lechner, M. et al. Notch2-mediated plasticity between marginal zone and follicular B cells. Nat. Commun. 12, 1111 (2021).
Article CAS PubMed PubMed Central Google Scholar
Graf, R. et al. BCR-dependent lineage plasticity in mature B cells. Science 363, 748–753 (2019).
Article CAS PubMed Google Scholar
Hernández, D. C. et al. An in vitro platform supports generation of human innate lymphoid cells from CD34(+) hematopoietic progenitors that recapitulate ex vivo identity. Immunity 54, 2417–2432.e2415 (2021).
Article PubMed CAS Google Scholar
De Obaldia, M. E. & Bhandoola, A. Transcriptional regulation of innate and adaptive lymphocyte lineages. Annu. Rev. Immunol. 33, 607–642 (2015).
Article PubMed CAS Google Scholar
Yang, Q. et al. T cell factor 1 is required for group 2 innate lymphoid cell generation. Immunity 38, 694–704 (2013).
Article CAS PubMed PubMed Central Google Scholar
Chea, S. et al. Single-cell gene expression analyses reveal heterogeneous responsiveness of fetal innate lymphoid progenitors to notch signaling. Cell Rep. 14, 1500–1516 (2016).
Article CAS PubMed Google Scholar
Perchet, T. et al. The notch signaling pathway is balancing type 1 innate lymphoid cell immune functions. Front. Immunol. 9, 1252 (2018).
Article PubMed PubMed Central CAS Google Scholar
Magri, G. et al. Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells. Nat. Immunol. 15, 354–364 (2014).
Article CAS PubMed PubMed Central Google Scholar
Foldi, J., Shang, Y., Zhao, B., Ivashkiv, L. B. & Hu, X. RBP-J is required for M2 macrophage polarization in response to chitin and mediates expression of a subset of M2 genes. Protein Cell 7, 201–209 (2016).
Article CAS PubMed PubMed Central Google Scholar
López-López, S. et al. NOTCH4 exhibits anti-inflammatory activity in activated macrophages by interfering with interferon-γ and TLR4 signaling. Front Immunol. 12, 734966 (2021).
Article PubMed PubMed Central Google Scholar
Zhou, J., Cheng, P., Youn, J. I., Cotter, M. J. & Gabrilovich, D. I. Notch and wingless signaling cooperate in regulation of dendritic cell differentiation. Immunity 30, 845–859 (2009).
Article CAS PubMed PubMed Central Google Scholar
Lewis, K. L. et al. Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity 35, 780–791 (2011).
Article CAS PubMed PubMed Central Google Scholar
Radke, A. L. et al. Mature human eosinophils express functional Notch ligands mediating eosinophil autocrine regulation. Blood 113, 3092–3101 (2009).
Article CAS PubMed PubMed Central Google Scholar
Hofmann, J. J. et al. Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome. Development 137, 4061–4072 (2010).
Article CAS PubMed PubMed Central Google Scholar
Antoniou, A. et al. Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9. Gastroenterology 136, 2325–2333 (2009).
Article PubMed CAS Google Scholar
Kageyama, S., Nakamura, K., Ke, B., Busuttil, R. W. & Kupiec-Weglinski, J. W. Serelaxin induces Notch1 signaling and alleviates hepatocellular damage in orthotopic liver transplantation. Am. J. Transpl. 18, 1755–1763 (2018).
Article CAS Google Scholar
Fiorotto, R. et al. Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice. J. Hepatol. 59, 124–130 (2013).
Article CAS PubMed PubMed Central Google Scholar
Cordero-Espinoza, L. et al. Dynamic cell contacts between periportal mesenchyme and ductal epithelium act as a rheostat for liver cell proliferation. Cell Stem Cell 28, 1907–1921 (2021).
Article CAS PubMed PubMed Central Google Scholar
Sayols, S. et al. Signalling codes for the maintenance and lineage commitment of embryonic gastric epithelial progenitors. Development 147, dev188839 (2020).
Jensen, J. et al. Control of endodermal endocrine development by Hes-1. Nat. Genet. 24, 36–44 (2000).
Article CAS PubMed Google Scholar
Sallé, J. et al. Intrinsic regulation of enteroendocrine fate by Numb. EMBO J. 36, 1928–1945 (2017).
Article PubMed PubMed Central CAS Google Scholar
Yin, X. et al. Niche-independent high-purity cultures of Lgr5+ intestinal stem cells and their progeny. Nat. Methods 11, 106–112 (2014).
Article CAS PubMed Google Scholar
Serra, D. et al. Self-organization and symmetry breaking in intestinal organoid development. Nature 569, 66–72 (2019).
Article CAS PubMed PubMed Central Google Scholar
Demitrack, E. S. et al. Notch signaling regulates gastric antral LGR5 stem cell function. EMBO J. 34, 2522–2536 (2015).
Article CAS PubMed PubMed Central Google Scholar
Gifford, G. B. et al. Notch1 and Notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis. Gut 66, 1001–1011 (2017).
Article CAS PubMed Google Scholar
Kim, T.-H. & Shivdasani, R. A. Notch signaling in stomach epithelial stem cell homeostasis. J. Exp. Med. 208, 677–688 (2011).
Article CAS PubMed PubMed Central Google Scholar
Apelqvist, A. et al. Notch signalling controls pancreatic cell differentiation. Nature 400, 877–881 (1999).
Article CAS PubMed Google Scholar
Fujikura, J. et al. Notch/Rbp-j signaling prevents premature endocrine and ductal cell differentiation in the pancreas. Cell Metab. 3, 59–65 (2006).
Article CAS PubMed Google Scholar
Rubey, M. et al. DLL1- and DLL4-mediated notch signaling is essential for adult pancreatic islet homeostasis. Diabetes 69, 915–926 (2020).
Article CAS PubMed Google Scholar
Seymour, P. A. et al. Jag1 modulates an oscillatory Dll1-Notch-Hes1 signaling module to coordinate growth and fate of pancreatic progenitors. Dev. Cell 52, 731–747 (2020).
Article CAS PubMed Google Scholar
Louvi, A. & Artavanis-Tsakonas, S. Notch signalling in vertebrate neural development. Nat. Rev. Neurosci. 7, 93–102 (2006).
Article CAS PubMed Google Scholar
Portin, P. & Rantanen, M. Interaction of master mind, big brain, neuralized and Notch genes of Drosophila melanogaster as expressed in adult morphology. Hereditas 114, 197–200 (1991).
Article CAS PubMed Google Scholar
Kelley, M. R., Kidd, S., Deutsch, W. A. & Young, M. W. Mutations altering the structure of epidermal growth factor-like coding sequences at the Drosophila Notch locus. Cell 51, 539–548 (1987).
Article CAS PubMed Google Scholar
Ye, Y., Lukinova, N. & Fortini, M. E. Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature 398, 525–529 (1999).
Article CAS PubMed Google Scholar
Zamboni, M., Llorens-Bobadilla, E., Magnusson, J. P. & Frisén, J. A widespread neurogenic potential of neocortical astrocytes is induced by injury. Cell Stem Cell 27, 605–617.e605 (2020).
Article CAS PubMed PubMed Central Google Scholar
Gao, F. et al. Transcription factor RBP-J-mediated signaling represses the differentiation of neural stem cells into intermediate neural progenitors. Mol. Cell Neurosci. 40, 442–450 (2009).
Article CAS PubMed Google Scholar
Chi, Z. et al. Botch promotes neurogenesis by antagonizing Notch. Dev. Cell 22, 707–720 (2012).
Article CAS PubMed PubMed Central Google Scholar
Mall, M. et al. Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates. Nature 544, 245–249 (2017).
Article CAS PubMed Google Scholar
Cárdenas, A. et al. Evolution of cortical neurogenesis in amniotes controlled by Robo signaling levels. Cell 174, 590–606.e521 (2018).
Article PubMed PubMed Central CAS Google Scholar
Lui, J. H., Hansen, D. V. & Kriegstein, A. R. Development and evolution of the human neocortex. Cell 146, 18–36 (2011).
Article CAS PubMed PubMed Central Google Scholar
Nichane, M., Ren, X., Souopgui, J. & Bellefroid, E. J. Hairy2 functions through both DNA-binding and non DNA-binding mechanisms at the neural plate border in Xenopus. Dev. Biol. 322, 368–380 (2008).
Article CAS PubMed Google Scholar
Ngan, E. S. et al. Hedgehog/Notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humans. J. Clin. Invest. 121, 3467–3478 (2011).
Article CAS PubMed PubMed Central Google Scholar
Tang, W. et al. Exome-wide association study identified new risk loci for Hirschsprung’s disease. Mol. Neurobiol. 54, 1777–1785 (2017).
Article CAS PubMed Google Scholar
Harima, Y., Takashima, Y., Ueda, Y., Ohtsuka, T. & Kageyama, R. Accelerating the tempo of the segmentation clock by reducing the number of introns in the Hes7 gene. Cell Rep. 3, 1–7 (2013).
Article CAS PubMed Google Scholar
Hussain, M. et al. Notch signaling: linking embryonic lung development and asthmatic airway remodeling. Mol. Pharm. 92, 676–693 (2017).
Article CAS Google Scholar
Tsao, P.-N. et al. Epithelial Notch signaling regulates lung alveolar morphogenesis and airway epithelial integrity. Proc. Natl Acad. Sci. USA 113, 8242–8247 (2016).
Article CAS PubMed PubMed Central Google Scholar
Rock, J. R. et al. Notch-dependent differentiation of adult airway basal stem cells. Cell Stem Cell 8, 639–648 (2011).
Article CAS PubMed PubMed Central Google Scholar
Pardo-Saganta, A. et al. Injury induces direct lineage segregation of functionally distinct airway basal stem/progenitor cell subpopulations. Cell Stem Cell 16, 184–197 (2015).
Article CAS PubMed PubMed Central Google Scholar
Singh, K. et al. JunB defines functional and structural integrity of the epidermo-pilosebaceous unit in the skin. Nat. Commun. 9, 3425 (2018).
Article PubMed PubMed Central CAS Google Scholar
Nguyen, B.-C. et al. Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev. 20, 1028–1042 (2006).
Article CAS PubMed PubMed Central Google Scholar
Ezratty, E. J. et al. A role for the primary cilium in Notch signaling and epidermal differentiation during skin development. Cell 145, 1129–1141 (2011).
Article CAS PubMed PubMed Central Google Scholar
Williams, S. E., Beronja, S., Pasolli, H. A. & Fuchs, E. Asymmetric cell divisions promote Notch-dependent epidermal differentiation. Nature 470, 353–358 (2011).
Article CAS PubMed PubMed Central Google Scholar
Veniaminova, N. A. et al. Niche-Specific Factors Dynamically Regulate Sebaceous Gland Stem Cells in the Skin. Dev. Cell 51, 326–340.e4 (2019).
Article CAS PubMed PubMed Central Google Scholar
Gratton, R. et al. Pleiotropic role of notch signaling in human skin diseases. Int. J. Mol. Sci. 21, 4214 (2020).
Wang, B. et al. Gamma-secretase gene mutations in familial acne inversa. Science 330, 1065 (2010).
Article CAS PubMed Google Scholar
Baudrimont, M., Dubas, F., Joutel, A., Tournier-Lasserve, E. & Bousser, M. G. Autosomal dominant leukoencephalopathy and subcortical ischemic stroke. A clinicopathological study. Stroke 24, 122–125 (1993).
Article CAS PubMed Google Scholar
Joutel, A. et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383, 707–710 (1996).
Article CAS PubMed Google Scholar
Joutel, A. et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 350, 1511–1515 (1997).
Article CAS PubMed Google Scholar
Monet-Leprêtre, M. et al. Abnormal recruitment of extracellular matrix proteins by excess Notch3 ECD: a new pathomechanism in CADASIL. Brain 136, 1830–1845 (2013).
Article PubMed PubMed Central Google Scholar
Okeda, R., Arima, K. & Kawai, M. Arterial changes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in relation to pathogenesis of diffuse myelin loss of cerebral white matter: examination of cerebral medullary arteries by reconstruction of serial sections of an autopsy case. Stroke 33, 2565–2569 (2002).
Article PubMed Google Scholar
Baron-Menguy, C., Domenga-Denier, V., Ghezali, L., Faraci, F. M. & Joutel, A. Increased Notch3 activity mediates pathological changes in structure of cerebral arteries. Hypertension 69, 60–70 (2017).
Article CAS PubMed Google Scholar
Dubroca, C. et al. Impaired vascular mechanotransduction in a transgenic mouse model of CADASIL arteriopathy. Stroke 36, 113–117 (2005).
Article PubMed Google Scholar
Ling, C. et al. Modeling CADASIL vascular pathologies with patient-derived induced pluripotent stem cells. Protein Cell 10, 249–271 (2019).
Article CAS PubMed PubMed Central Google Scholar
Joutel, A. et al. Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease. J. Clin. Invest. 120, 433–445 (2010).
Article CAS PubMed PubMed Central Google Scholar
McDaniell, R. et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am. J. Hum. Genet. 79, 169–173 (2006).
Article CAS PubMed PubMed Central Google Scholar
Lykavieris, P., Hadchouel, M., Chardot, C. & Bernard, O. Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. Gut 49, 431–435 (2001).
Article CAS PubMed PubMed Central Google Scholar
Fabris, L. et al. Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases. Nat. Rev. Gastroenterol. Hepatol. 16, 497–511 (2019).
Article PubMed PubMed Central Google Scholar
Colliton, R. P. et al. Mutation analysis of Jagged1 (JAG1) in Alagille syndrome patients. Hum. Mutat. 17, 151–152 (2001).
Article CAS PubMed Google Scholar
Warthen, D. M. et al. Jagged1 (JAG1) mutations in Alagille syndrome: increasing the mutation detection rate. Hum. Mutat. 27, 436–443 (2006).
Article CAS PubMed Google Scholar
Suskind, D. L. & Murray, K. F. Increasing the mutation rate for Jagged1 mutations in patients with Alagille syndrome. Hepatology 46, 598–599 (2007).
Article PubMed Google Scholar
Kamath, B. M., Spinner, N. B. & Rosenblum, N. D. Renal involvement and the role of Notch signalling in Alagille syndrome. Nat. Rev. Nephrol. 9, 409–418 (2013).
Article CAS PubMed Google Scholar
Huch, M. et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 160, 299–312 (2015).
Article CAS PubMed PubMed Central Google Scholar
Andersson, E. R. et al. Mouse model of alagille syndrome and mechanisms of Jagged1 Missense mutations. Gastroenterology 154, 1080–1095 (2018).
Article CAS PubMed Google Scholar
Adams, J. M. & Jafar-Nejad, H. A new model of alagille syndrome with broad phenotypic representation. Gastroenterology 154, 803–806 (2018).
Article PubMed Google Scholar
Adams, J. M. et al. Sox9 is a modifier of the liver disease severity in a mouse model of alagille syndrome. Hepatology 71, 1331–1349 (2020).
Article CAS PubMed Google Scholar
Pourquié, O. Vertebrate segmentation: from cyclic gene networks to scoliosis. Cell 145, 650–663 (2011).
Article PubMed PubMed Central CAS Google Scholar
Lefebvre, M. et al. Diagnostic strategy in segmentation defect of the vertebrae: a retrospective study of 73 patients. J. Med. Genet. 55, 422–429 (2018).
Article CAS PubMed Google Scholar
Dunwoodie, S. L. The role of Notch in patterning the human vertebral column. Curr. Opin. Genet. Dev. 19, 329–337 (2009).
Article CAS PubMed Google Scholar
Kusumi, K. et al. The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries. Nat. Genet. 19, 274–278 (1998).
Article CAS PubMed Google Scholar
Bulman, M. P. et al. Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nat. Genet. 24, 438–441 (2000).
Article CAS PubMed Google Scholar
Whittock, N. V. et al. Mutated MESP2 causes spondylocostal dysostosis in humans. Am. J. Hum. Genet. 74, 1249–1254 (2004).
Article CAS PubMed PubMed Central Google Scholar
Makino, Y. et al. Spatiotemporal disorder in the axial skeleton development of the Mesp2-null mouse: a model of spondylocostal dysostosis and spondylothoracic dysostosis. Bone 53, 248–258 (2013).
Article CAS PubMed Google Scholar
Sparrow, D. B., Sillence, D., Wouters, M. A., Turnpenny, P. D. & Dunwoodie, S. L. Two novel missense mutations in HAIRY-AND-ENHANCER-OF-SPLIT-7 in a family with spondylocostal dysostosis. Eur. J. Hum. Genet. 18, 674–679 (2010).
Article CAS PubMed PubMed Central Google Scholar
Sparrow, D. B. et al. Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype. Am. J. Hum. Genet. 78, 28–37 (2006).
Article CAS PubMed Google Scholar
Sparrow, D. B. et al. A mechanism for gene-environment interaction in the etiology of congenital scoliosis. Cell 149, 295–306 (2012).
Article CAS PubMed Google Scholar
Valenti, L. et al. Hepatic notch signaling correlates with insulin resistance and nonalcoholic fatty liver disease. Diabetes 62, 4052–4062 (2013).
Article CAS PubMed PubMed Central Google Scholar
Zhu, C., Tabas, I., Schwabe, R. F. & Pajvani, U. B. Maladaptive regeneration—the reawakening of developmental pathways in NASH and fibrosis. Nat. Rev. Gastroenterol. Hepatol. 18, 131–142 (2021).
Article PubMed Google Scholar
Romeo, S. Notch and Nonalcoholic Fatty Liver and Fibrosis. N. Engl. J. Med. 380, 681–683 (2019).
Article PubMed Google Scholar
Yu, J. et al. Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis. Sci. Transl. Med. 13, eabe1692 (2021).
Zhu, C. et al. Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis. Sci. Transl. Med. 10, eaat0344 (2018).
Sassi, N. et al. The role of the Notch pathway in healthy and osteoarthritic articular cartilage: from experimental models to ex vivo studies. Arthritis Res. Ther. 13, 208 (2011).
Article CAS PubMed PubMed Central Google Scholar
Monteagudo, S. & Lories, R. J. A Notch in the joint that exacerbates osteoarthritis. Nat. Rev. Rheumatol. 14, 563–564 (2018).
Article PubMed Google Scholar
Liu, Z. et al. A dual role for NOTCH signaling in joint cartilage maintenance and osteoarthritis. Sci. Signal 8, ra71 (2015).
Article PubMed PubMed Central CAS Google Scholar
Sun, J. et al. Notch ligand Jagged1 promotes mesenchymal stromal cell-based cartilage repair. Exp. Mol. Med. 50, 1–10 (2018).
Article PubMed CAS Google Scholar
Hosaka, Y. et al. Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development. Proc. Natl Acad. Sci. USA 110, 1875–1880 (2013).
Article CAS PubMed PubMed Central Google Scholar
Tindemans, I. et al. Increased surface expression of NOTCH on memory T cells in peripheral blood from patients with asthma. J. Allergy Clin. Immunol. 143, 769–771.e3 (2019).
Article CAS PubMed Google Scholar
Tindemans, I. et al. Notch signaling in T cells is essential for allergic airway inflammation, but expression of the Notch ligands Jagged 1 and Jagged 2 on dendritic cells is dispensable. J. Allergy Clin. Immunol. 140, 1079–1089 (2017).
Article CAS PubMed Google Scholar
Huang, M.-T., Chiu, C.-J. & Chiang, B.-L. Multi-faceted notch in allergic airway inflammation. Int. J. Mol. Sci. 20, 3508 (2019).
KleinJan, A. et al. The Notch pathway inhibitor stapled α-helical peptide derived from mastermind-like 1 (SAHM1) abrogates the hallmarks of allergic asthma. J. Allergy Clin. Immunol. 142, 76–85.e8 (2018).
Article CAS PubMed Google Scholar
Tindemans, I. et al. Notch signaling licenses allergic airway inflammation by promoting Th2 cell lymph node egress. J. Clin. Investig. 130, 3576–3591 (2020).
Article CAS PubMed PubMed Central Google Scholar
Harb, H. et al. A regulatory T cell Notch4-GDF15 axis licenses tissue inflammation in asthma. Nat. Immunol. 21, 1359–1370 (2020).
Article CAS PubMed PubMed Central Google Scholar
Cao, Z. et al. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis. Nat. Med. 22, 154–162 (2016).
Article CAS PubMed PubMed Central Google Scholar
Steffes, L. C. et al. A Notch3-marked subpopulation of vascular smooth muscle cells is the cell of origin for occlusive pulmonary vascular lesions. Circulation 142, 1545–1561 (2020).
Article CAS PubMed PubMed Central Google Scholar
Dabral, S. et al. Notch1 signalling regulates endothelial proliferation and apoptosis in pulmonary arterial hypertension. Eur. Respir. J. 48, 1137–1149 (2016).
Article CAS PubMed Google Scholar
Gu, X.-Y., Chu, X., Zeng, X.-L., Bao, H.-R. & Liu, X.-J. Effects of PM2.5 exposure on the Notch signaling pathway and immune imbalance in chronic obstructive pulmonary disease. Environ. Pollut. 226, 163–173 (2017).
Article CAS PubMed Google Scholar
Bodas, M. et al. Cigarette smoke activates NOTCH3 to promote goblet cell differentiation in human airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 64, 426–440 (2021).
Article CAS PubMed PubMed Central Google Scholar
Ballester-López, C. et al. The Notch ligand DNER regulates macrophage IFNγ release in chronic obstructive pulmonary disease. EBioMedicine 43, 562–575 (2019).
Article PubMed PubMed Central Google Scholar
Di Ianni, M. et al. NOTCH and graft-versus-host disease. Front. Immunol. 9, 1825 (2018).
Article PubMed PubMed Central CAS Google Scholar
Radojcic, V. et al. Notch signaling mediated by Delta-like ligands 1 and 4 controls the pathogenesis of chronic GVHD in mice. Blood 132, 2188–2200 (2018).
Article CAS PubMed PubMed Central Google Scholar
Yvon, E. S. et al. Overexpression of the Notch ligand, Jagged-1, induces alloantigen-specific human regulatory T cells. Blood 102, 3815–3821 (2003).
Article CAS PubMed Google Scholar
Amsen, D. T cells take directions from supporting cast in graft-versus-host disease. J. Clin. Investig. 127, 1215–1217 (2017).
Article PubMed PubMed Central Google Scholar
Poe, J. C. et al. An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD. Blood 130, 2131–2145 (2017).
Article CAS PubMed PubMed Central Google Scholar
Bartolome, A., Zhu, C., Sussel, L. & Pajvani, U. B. Notch signaling dynamically regulates adult β cell proliferation and maturity. J. Clin. Invest. 129, 268–280 (2019).
Article PubMed Google Scholar
Reynolds, T. C., Smith, S. D. & Sklar, J. Analysis of DNA surrounding the breakpoints of chromosomal translocations involving the beta T cell receptor gene in human lymphoblastic neoplasms. Cell 50, 107–117 (1987).
Article CAS PubMed Google Scholar
Ellisen, L. W. et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66, 649–661 (1991).
Article CAS PubMed Google Scholar
Weng, A. P. et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306, 269–271 (2004).
Article CAS PubMed Google Scholar
Pear, W. S. et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J. Exp. Med. 183, 2283–2291 (1996).
Article CAS PubMed Google Scholar
Herranz, D. et al. A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Nat. Med. 20, 1130–1137 (2014).
Article CAS PubMed PubMed Central Google Scholar
Herranz, D. et al. Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia. Nat. Med. 21, 1182–1189 (2015).
Article CAS PubMed PubMed Central Google Scholar
Trimarchi, T. et al. Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia. Cell 158, 593–606 (2014).
Article CAS PubMed PubMed Central Google Scholar
Joshi, I. et al. Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases. Blood 113, 1689–1698 (2009).
Article CAS PubMed PubMed Central Google Scholar
Bernasconi-Elias, P. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016).
Article CAS PubMed PubMed Central Google Scholar
Bonfiglio, F. et al. Genetic and phenotypic attributes of splenic marginal zone lymphoma. Blood 139, 732–747 (2021).
Article CAS Google Scholar
Tardivon, D. et al. Notch signaling promotes disease initiation and progression in murine chronic lymphocytic leukemia. Blood 137, 3079–3092 (2021).
Article CAS PubMed Google Scholar
Huang, Y.-H. et al. CREBBP/EP300 mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-associated macrophage polarization via FBXW7-NOTCH-CCL2/CSF1 axis. Signal Transduct. Target Ther. 6, 10 (2021).
Article CAS PubMed PubMed Central Google Scholar
Kannan, S. et al. Notch activation inhibits AML growth and survival: a potential therapeutic approach. J. Exp. Med. 210, 321–337 (2013).
Article CAS PubMed PubMed Central Google Scholar
Yuan, X. et al. Meta-analysis reveals the correlation of Notch signaling with non-small cell lung cancer progression and prognosis. Sci. Rep. 5, 10338 (2015).
Article PubMed PubMed Central Google Scholar
Liu, L. et al. An RFC4/Notch1 signaling feedback loop promotes NSCLC metastasis and stemness. Nat. Commun. 12, 2693 (2021).
Article CAS PubMed PubMed Central Google Scholar
Westhoff, B. et al. Alterations of the Notch pathway in lung cancer. Proc. Natl Acad. Sci. USA 106, 22293–22298 (2009).
Article CAS PubMed PubMed Central Google Scholar
Licciulli, S. et al. Notch1 is required for Kras-induced lung adenocarcinoma and controls tumor cell survival via p53. Cancer Res 73, 5974–5984 (2013).
Article CAS PubMed PubMed Central Google Scholar
Xu, X. et al. The cell of origin and subtype of K-Ras-induced lung tumors are modified by Notch and Sox2. Genes Dev. 28, 1929–1939 (2014).
Article CAS PubMed PubMed Central Google Scholar
Allen, T. D., Rodriguez, E. M., Jones, K. D. & Bishop, J. M. Activated Notch1 induces lung adenomas in mice and cooperates with Myc in the generation of lung adenocarcinoma. Cancer Res. 71, 6010–6018 (2011).
Article CAS PubMed PubMed Central Google Scholar
Ali, S. A., Justilien, V., Jamieson, L., Murray, N. R. & Fields, A. P. Protein kinase Cι drives a NOTCH3-dependent Stem-like phenotype in mutant KRAS lung adenocarcinoma. Cancer Cell 29, 367–378 (2016).
Article CAS PubMed PubMed Central Google Scholar
Sinicropi-Yao, S. L. et al. Co-expression analysis reveals mechanisms underlying the varied roles of NOTCH1 in NSCLC. J. Thorac. Oncol. 14, 223–236 (2019).
Article CAS PubMed Google Scholar
Qiao, L. & Wong, B. C. Role of Notch signaling in colorectal cancer. Carcinogenesis 30, 1979–1986 (2009).
Article CAS PubMed Google Scholar
Tyagi, A., Sharma, A. K. & Damodaran, C. A review on Notch signaling and colorectal cancer. Cells 9, 1549 (2020).
Fre, S. et al. Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine. Proc. Natl Acad. Sci. USA 106, 6309–6314 (2009).
Article CAS PubMed PubMed Central Google Scholar
Hayakawa, Y. et al. BHLHA15-positive secretory precursor cells can give rise to tumors in intestine and colon in mice. Gastroenterology 156, 1066–1081.e1016 (2019).
Article CAS PubMed Google Scholar
Jackstadt, R. et al. Epithelial NOTCH signaling rewires the tumor microenvironment of colorectal cancer to drive poor-prognosis subtypes and metastasis. Cancer Cell 36, 319–336.e317 (2019).
Article CAS PubMed PubMed Central Google Scholar
Bu, P. et al. A miR-34a-numb feedforward loop triggered by inflammation regulates asymmetric stem cell division in intestine and colon cancer. Cell Stem Cell 18, 189–202 (2016).
Article CAS PubMed PubMed Central Google Scholar
Ruland, J. Colon cancer: epithelial notch signaling recruits neutrophils to drive metastasis. Cancer Cell 36, 213–214 (2019).
Article CAS PubMed Google Scholar
Sonoshita, M. et al. Promotion of colorectal cancer invasion and metastasis through activation of NOTCH-DAB1-ABL-RHOGEF protein TRIO. Cancer Discov. 5, 198–211 (2015).
Article CAS PubMed Google Scholar
Jackstadt, R. & Sansom, O. J. Mouse models of intestinal cancer. J. Pathol. 238, 141–151 (2016).
Article PubMed Google Scholar
Kranenburg, O. Prometastatic NOTCH signaling in colon cancer. Cancer Discov. 5, 115–117 (2015).
Article CAS PubMed Google Scholar
Chanrion, M. et al. Concomitant Notch activation and p53 deletion trigger epithelial-to-mesenchymal transition and metastasis in mouse gut. Nat. Commun. 5, 5005 (2014).
Article CAS PubMed Google Scholar
Sonoshita, M. et al. Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling. Cancer Cell 19, 125–137 (2011).
Article CAS PubMed Google Scholar
Parida, S. et al. A procarcinogenic colon microbe promotes breast tumorigenesis and metastatic progression and concomitantly activates Notch and β-Catenin Axes. Cancer Discov. 11, 1138–1157 (2021).
Article CAS PubMed Google Scholar
Nabet, B. Y. et al. Exosome RNA unshielding couples stromal activation to pattern recognition receptor signaling in cancer. Cell 170, 352–366.e313 (2017).
Article CAS PubMed PubMed Central Google Scholar
Krishna, B. M. et al. Notch signaling in breast cancer: from pathway analysis to therapy. Cancer Lett. 461, 123–131 (2019).
Article CAS PubMed PubMed Central Google Scholar
Gallahan, D., Kozak, C. & Callahan, R. A new common integration region (int-3) for mouse mammary tumor virus on mouse chromosome 17. J. Virol. 61, 218–220 (1987).
Article CAS PubMed PubMed Central Google Scholar
Reedijk, M. et al. High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res. 65, 8530–8537 (2005).
Article CAS PubMed Google Scholar
Callahan, R. & Smith, G. H. MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways. Oncogene 19, 992–1001 (2000).
Article CAS PubMed Google Scholar
Theodorou, V. et al. MMTV insertional mutagenesis identifies genes, gene families and pathways involved in mammary cancer. Nat. Genet. 39, 759–769 (2007).
Article CAS PubMed Google Scholar
Robinson, D. R. et al. Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer. Nat. Med. 17, 1646–1651 (2011).
Article CAS PubMed PubMed Central Google Scholar
Jordan, N. V. et al. HER2 expression identifies dynamic functional states within circulating breast cancer cells. Nature 537, 102–106 (2016).
Article CAS PubMed PubMed Central Google Scholar
Colaluca, I. N. et al. NUMB controls p53 tumour suppressor activity. Nature 451, 76–80 (2008).
Article CAS PubMed Google Scholar
Dittmer, J. Breast cancer stem cells: features, key drivers and treatment options. Semin. Cancer Biol. 53, 59–74 (2018).
Article PubMed Google Scholar
Ibrahim, S. A. et al. Syndecan-1 is a novel molecular marker for triple negative inflammatory breast cancer and modulates the cancer stem cell phenotype via the IL-6/STAT3, Notch and EGFR signaling pathways. Mol. Cancer 16, 57 (2017).
Article PubMed PubMed Central CAS Google Scholar
Shen, Q. et al. Notch shapes the innate immunophenotype in breast cancer. Cancer Discov. 7, 1320–1335 (2017).
Article CAS PubMed Google Scholar
Lin, Q. et al. ASPH-notch axis guided exosomal delivery of prometastatic secretome renders breast cancer multi-organ metastasis. Mol. Cancer 18, 156 (2019).
Article CAS PubMed PubMed Central Google Scholar
The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).
Lu, K. H. et al. Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis. Clin. Cancer Res. 10, 3291–3300 (2004).
Article CAS PubMed Google Scholar
Park, J. T. et al. Notch3 gene amplification in ovarian cancer. Cancer Res. 66, 6312–6318 (2006).
Article CAS PubMed Google Scholar
Hopfer, O., Zwahlen, D., Fey, M. F. & Aebi, S. The Notch pathway in ovarian carcinomas and adenomas. Br. J. Cancer 93, 709–718 (2005).
Article CAS PubMed PubMed Central Google Scholar
Groeneweg, J. W., Foster, R., Growdon, W. B., Verheijen, R. H. & Rueda, B. R. Notch signaling in serous ovarian cancer. J. Ovarian Res. 7, 95 (2014).
Article PubMed PubMed Central CAS Google Scholar
Park, J. T. et al. Notch3 overexpression is related to the recurrence of ovarian cancer and confers resistance to carboplatin. Am. J. Pathol. 177, 1087–1094 (2010).
Article CAS PubMed PubMed Central Google Scholar
Choi, J. H. et al. Jagged-1 and Notch3 juxtacrine loop regulates ovarian tumor growth and adhesion. Cancer Res. 68, 5716–5723 (2008).
Article CAS PubMed PubMed Central Google Scholar
Steg, A. D. et al. Targeting the notch ligand JAGGED1 in both tumor cells and stroma in ovarian cancer. Clin. Cancer Res 17, 5674–5685 (2011).
Article CAS PubMed PubMed Central Google Scholar
Yen, W. C. et al. Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clin. Cancer Res. 21, 2084–2095 (2015).
Article CAS PubMed Google Scholar
Hu, W. et al. Biological roles of the Delta family Notch ligand Dll4 in tumor and endothelial cells in ovarian cancer. Cancer Res 71, 6030–6039 (2011).
Article CAS PubMed PubMed Central Google Scholar
Zhu, C. et al. Notch activity characterizes a common hepatocellular carcinoma subtype with unique molecular and clinicopathologic features. J. Hepatol. 74, 613–626 (2021).
Article CAS PubMed Google Scholar
Razumilava, N. & Gores, G. J. Notch-driven carcinogenesis: the merging of hepatocellular cancer and cholangiocarcinoma into a common molecular liver cancer subtype. J. Hepatol. 58, 1244–1245 (2013).
Article PubMed Google Scholar
Villanueva, A. et al. Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology 143, 1660–1669.e1667 (2012).
Article CAS PubMed Google Scholar
Zhang, L. et al. An essential role of RNF187 in Notch1 mediated metastasis of hepatocellular carcinoma. J. Exp. Clin. Cancer Res 38, 384 (2019).
Article PubMed PubMed Central CAS Google Scholar
Viatour, P. et al. Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. J. Exp. Med. 208, 1963–1976 (2011).
Article CAS PubMed PubMed Central Google Scholar
Luiken, S. et al. NOTCH target gene HES5 mediates oncogenic and tumor suppressive functions in hepatocarcinogenesis. Oncogene 39, 3128–3144 (2020).
Article CAS PubMed PubMed Central Google Scholar
Lim, S. O. et al. Notch1 differentially regulates oncogenesis by wildtype p53 overexpression and p53 mutation in grade III hepatocellular carcinoma. Hepatology 53, 1352–1362 (2011).
Article CAS PubMed Google Scholar
Hu, Y. Y. et al. Notch signaling contributes to the maintenance of both normal neural stem cells and patient-derived glioma stem cells. BMC Cancer 11, 82 (2011).
Article CAS PubMed PubMed Central Google Scholar
Zhu, T. S. et al. Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. Cancer Res. 71, 6061–6072 (2011).
Article CAS PubMed PubMed Central Google Scholar
Chu, Q., Orr, B. A., Semenkow, S., Bar, E. E. & Eberhart, C. G. Prolonged inhibition of glioblastoma xenograft initiation and clonogenic growth following in vivo Notch blockade. Clin. Cancer Res. 19, 3224–3233 (2013).
Article CAS PubMed PubMed Central Google Scholar
Natarajan, S. et al. Notch1-induced brain tumor models the sonic hedgehog subgroup of human medulloblastoma. Cancer Res. 73, 5381–5390 (2013).
Article CAS PubMed PubMed Central Google Scholar
Wang, J. et al. Invasion of white matter tracts by glioma stem cells is regulated by a NOTCH1-SOX2 positive-feedback loop. Nat. Neurosci. 22, 91–105 (2019).
Article CAS PubMed Google Scholar
Katsushima, K. et al. Targeting the Notch-regulated non-coding RNA TUG1 for glioma treatment. Nat. Commun. 7, 13616 (2016).
Article PubMed PubMed Central Google Scholar
Yi, L. et al. Notch1 signaling pathway promotes invasion, self-renewal and growth of glioma initiating cells via modulating chemokine system CXCL12/CXCR4. J. Exp. Clin. Cancer Res. 38, 339 (2019).
Article PubMed PubMed Central CAS Google Scholar
Giachino, C. et al. A tumor suppressor function for notch signaling in forebrain tumor subtypes. Cancer Cell 28, 730–742 (2015).
Article CAS PubMed Google Scholar
Parmigiani, E., Taylor, V. & Giachino, C. Oncogenic and tumor-suppressive functions of NOTCH signaling in glioma. Cells 9 (2020).
Stephens, P. J. et al. Whole exome sequencing of adenoid cystic carcinoma. J. Clin. Invest. 123, 2965–2968 (2013).
Article CAS PubMed PubMed Central Google Scholar
Ho, A. S. et al. The mutational landscape of adenoid cystic carcinoma. Nat. Genet. 45, 791–798 (2013).
Article CAS PubMed PubMed Central Google Scholar
Drier, Y. et al. An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma. Nat. Genet. 48, 265–272 (2016).
Article CAS PubMed PubMed Central Google Scholar
Karpinets, T. V. et al. Whole-genome sequencing of common salivary gland carcinomas: subtype-restricted and shared genetic alterations. Clin. Cancer Res. 27, 3960–3969 (2021).
Article CAS PubMed PubMed Central Google Scholar
Xie, M. et al. Alterations of Notch pathway in patients with adenoid cystic carcinoma of the trachea and its impact on survival. Lung Cancer 121, 41–47 (2018).
Article PubMed Google Scholar
Ferrarotto, R. et al. A phase I dose-escalation and dose-expansion study of brontictuzumab in subjects with selected solid tumors. Ann. Oncol. 29, 1561–1568 (2018).
Article CAS PubMed Google Scholar
Ferrarotto, R. et al. Proteogenomic analysis of salivary adenoid cystic carcinomas defines molecular subtypes and identifies therapeutic targets. Clin. Cancer Res. 27, 852–864 (2021).
Article CAS PubMed Google Scholar
Bhagat, T. D. et al. Notch pathway is activated via genetic and epigenetic alterations and is a therapeutic target in clear cell renal cancer. J. Biol. Chem. 292, 837–846 (2017).
Article CAS PubMed Google Scholar
Nowell, C. S. & Radtke, F. Notch as a tumour suppressor. Nat. Rev. Cancer 17, 145–159 (2017).
Article CAS PubMed Google Scholar
Oronsky, B., Ma, P. C., Morgensztern, D. & Carter, C. A. Nothing But NET: a review of neuroendocrine tumors and carcinomas. Neoplasia 19, 991–1002 (2017).
Article CAS PubMed PubMed Central Google Scholar
Hu, J. et al. Comprehensive genomic profiling of small cell lung cancer in Chinese patients and the implications for therapeutic potential. Cancer Med. 8, 4338–4347 (2019).
Article CAS PubMed PubMed Central Google Scholar
Quintanal-Villalonga, A. et al. Multi-omic analysis of lung tumors defines pathways activated in neuroendocrine transformation. Cancer Discov 11, 3028–3047 (2021).
Article CAS PubMed Google Scholar
Saunders, L. R. et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci. Transl. Med. 7, 302ra136 (2015).
Article PubMed PubMed Central CAS Google Scholar
Xie, H. et al. Expression of delta-like protein 3 is reproducibly present in a subset of small cell lung carcinomas and pulmonary carcinoid tumors. Lung Cancer 135, 73–79 (2019).
Article PubMed Google Scholar
Gazdar, A. F., Bunn, P. A. & Minna, J. D. Small-cell lung cancer: what we know, what we need to know and the path forward. Nat. Rev. Cancer 17, 725–737 (2017).
Article CAS PubMed Google Scholar
George, J. et al. Comprehensive genomic profiles of small cell lung cancer. Nature 524, 47–53 (2015).
Article CAS PubMed PubMed Central Google Scholar
Kunnimalaiyaan, M., Vaccaro, A. M., Ndiaye, M. A. & Chen, H. Overexpression of the NOTCH1 intracellular domain inhibits cell proliferation and alters the neuroendocrine phenotype of medullary thyroid cancer cells. J. Biol. Chem. 281, 39819–39830 (2006).
Article CAS PubMed Google Scholar
Wang, H., Chen, Y., Fernandez-Del Castillo, C., Yilmaz, O. & Deshpande, V. Heterogeneity in signaling pathways of gastroenteropancreatic neuroendocrine tumors: a critical look at notch signaling pathway. Mod. Pathol. 26, 139–147 (2013).
Article CAS PubMed Google Scholar
Rekhtman, N. et al. Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets. Clin. Cancer Res. 22, 3618–3629 (2016).
Article CAS PubMed PubMed Central Google Scholar
Borromeo, M. D. et al. ASCL1 and NEUROD1 reveal heterogeneity in pulmonary neuroendocrine tumors and regulate distinct genetic programs. Cell Rep. 16, 1259–1272 (2016).
Article CAS PubMed PubMed Central Google Scholar
Meder, L. et al. NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas. Int. J. Cancer 138, 927–938 (2016).
Article CAS PubMed Google Scholar
Wyche, T. P. et al. Thiocoraline activates the Notch pathway in carcinoids and reduces tumor progression in vivo. Cancer Gene Ther. 21, 518–525 (2014).
Article CAS PubMed PubMed Central Google Scholar
Ouadah, Y. et al. Rare pulmonary neuroendocrine cells are stem cells regulated by Rb, p53, and Notch. Cell 179, 403–416.e23 (2019).
Article CAS PubMed PubMed Central Google Scholar
Stransky, N. et al. The mutational landscape of head and neck squamous cell carcinoma. Science 333, 1157–1160 (2011).
Article CAS PubMed PubMed Central Google Scholar
Natsuizaka, M. et al. Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma. Nat. Commun. 8, 1758 (2017).
Article PubMed PubMed Central CAS Google Scholar
Al Labban, D. et al. Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B. J. Clin. Investig. 128, 2581–2599 (2018).
Article PubMed PubMed Central Google Scholar
Agrawal, N. et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 333, 1154–1157 (2011).
Article CAS PubMed PubMed Central Google Scholar
Fukusumi, T. & Califano, J. A. The NOTCH pathway in head and neck squamous cell carcinoma. J. Dent. Res 97, 645–653 (2018).
Article CAS PubMed PubMed Central Google Scholar
South, A. P. et al. NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis. J. Invest. Dermatol. 134, 2630–2638 (2014).
Article CAS PubMed PubMed Central Google Scholar
Wang, N. J. et al. Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma. Proc. Natl Acad. Sci. USA 108, 17761–17766 (2011).
Article CAS PubMed PubMed Central Google Scholar
Rampias, T. et al. A new tumor suppressor role for the Notch pathway in bladder cancer. Nat. Med. 20, 1199–1205 (2014).
Article CAS PubMed Google Scholar
Gao, Y. B. et al. Genetic landscape of esophageal squamous cell carcinoma. Nat. Genet. 46, 1097–1102 (2014).
Article CAS PubMed Google Scholar
Agrawal, N. et al. Comparative genomic analysis of esophageal adenocarcinoma and squamous cell carcinoma. Cancer Discov. 2, 899–905 (2012).
Article CAS PubMed PubMed Central Google Scholar
Khelil, M. et al. Delta-like ligand-Notch1 signaling is selectively modulated by HPV16 E6 to promote squamous cell proliferation and correlates with cervical cancer prognosis. Cancer Res. 81, 1909–1921 (2021).
Article CAS PubMed Google Scholar
Nassar, D., Latil, M., Boeckx, B., Lambrechts, D. & Blanpain, C. Genomic landscape of carcinogen-induced and genetically induced mouse skin squamous cell carcinoma. Nat. Med. 21, 946–954 (2015).
Article CAS PubMed Google Scholar
Nicolas, M. et al. Notch1 functions as a tumor suppressor in mouse skin. Nat. Genet. 33, 416–421 (2003).
Article CAS PubMed Google Scholar
Proweller, A. et al. Impaired notch signaling promotes de novo squamous cell carcinoma formation. Cancer Res. 66, 7438–7444 (2006).
Article CAS PubMed Google Scholar
Extance, A. Alzheimer’s failure raises questions about disease-modifying strategies. Nat. Rev. Drug Discov. 9, 749–751 (2010).
Article CAS PubMed Google Scholar
Quan, X. X. et al. Targeting Notch1 and IKKα enhanced NF-κB activation in CD133(+) skin cancer stem cells. Mol. Cancer Ther. 17, 2034–2048 (2018).
Article CAS PubMed PubMed Central Google Scholar
Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016).
Article CAS PubMed Google Scholar
Avila, J. L. & Kissil, J. L. Notch signaling in pancreatic cancer: oncogene or tumor suppressor? Trends Mol. Med. 19, 320–327 (2013).
Article CAS PubMed PubMed Central Google Scholar
Hanlon, L. et al. Notch1 functions as a tumor suppressor in a model of K-ras-induced pancreatic ductal adenocarcinoma. Cancer Res. 70, 4280–4286 (2010).
Article CAS PubMed PubMed Central Google Scholar
Plentz, R. et al. Inhibition of gamma-secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma. Gastroenterology 136, 1741–1749.e1746 (2009).
Article CAS PubMed Google Scholar
Maniati, E. et al. Crosstalk between the canonical NF-κB and Notch signaling pathways inhibits Pparγ expression and promotes pancreatic cancer progression in mice. J. Clin. Invest. 121, 4685–4699 (2011).
Article CAS PubMed PubMed Central Google Scholar
Cook, N. et al. Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma. J. Exp. Med. 209, 437–444 (2012).
Article CAS PubMed PubMed Central Google Scholar
Anderson, N. M. & Simon, M. C. The tumor microenvironment. Curr. Biol. 30, R921–r925 (2020).
Article CAS PubMed PubMed Central Google Scholar
Bejarano, L., Jordāo, M. J. C. & Joyce, J. A. Therapeutic targeting of the tumor microenvironment. Cancer Disco. 11, 933–959 (2021).
Article CAS Google Scholar
Meurette, O. & Mehlen, P. Notch signaling in the tumor microenvironment. Cancer Cell 34, 536–548 (2018).
Article CAS PubMed Google Scholar
Hinshaw, D. C. & Shevde, L. A. The tumor microenvironment innately modulates cancer progression. Cancer Res. 79, 4557–4566 (2019).
Article CAS PubMed PubMed Central Google Scholar
Tchekneva, E. E. et al. Determinant roles of dendritic cell-expressed Notch Delta-like and Jagged ligands on anti-tumor T cell immunity. J. Immunother. Cancer 7, 95 (2019).
Article PubMed PubMed Central Google Scholar
Wang, L. et al. Notch-regulated dendritic cells restrain inflammation-associated colorectal carcinogenesis. Cancer Immunol. Res. 9, 348–361 (2021).
Article CAS PubMed PubMed Central Google Scholar
Kirkling, M. E. et al. Notch signaling facilitates in vitro generation of cross-presenting classical dendritic cells. Cell Rep. 23, 3658–3672.e3656 (2018).
Article CAS PubMed PubMed Central Google Scholar
Balan, S. et al. Large-scale human dendritic cell differentiation revealing notch-dependent lineage bifurcation and heterogeneity. Cell Rep. 24, 1902–1915.e1906 (2018).
Article CAS PubMed PubMed Central Google Scholar
Guilliams, M. & Scott, C. L. ‘NOTCHing up’ the in vitro production of dendritic cells. Trends Immunol. 39, 765–767 (2018).
Article CAS PubMed Google Scholar
Cho, O. H. et al. Notch regulates cytolytic effector function in CD8+ T cells. J. Immunol. 182, 3380–3389 (2009).
Article CAS PubMed Google Scholar
Maekawa, Y. et al. Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity. Nat. Immunol. 9, 1140–1147 (2008).
Article CAS PubMed Google Scholar
Backer, R. A. et al. A central role for Notch in effector CD8(+) T cell differentiation. Nat. Immunol. 15, 1143–1151 (2014).
Article CAS PubMed PubMed Central Google Scholar
Kuijk, L. M. et al. Notch controls generation and function of human effector CD8+ T cells. Blood 121, 2638–2646 (2013).
Article CAS PubMed Google Scholar
Huang, Y. et al. Resuscitating cancer immunosurveillance: selective stimulation of DLL1-Notch signaling in T cells rescues T-cell function and inhibits tumor growth. Cancer Res. 71, 6122–6131 (2011).
Article CAS PubMed PubMed Central Google Scholar
Sorrentino, C. et al. Adenosine A2A receptor stimulation inhibits tcr-induced Notch1 activation in CD8+T-cells. Front. Immunol. 10, 162 (2019).
Article CAS PubMed PubMed Central Google Scholar
Hombrink, P. et al. Programs for the persistence, vigilance and control of human CD8(+) lung-resident memory T cells. Nat. Immunol. 17, 1467–1478 (2016).
Article CAS PubMed Google Scholar
Savas, P. et al. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat. Med. 24, 986–993 (2018).
Article CAS PubMed Google Scholar
Cho, J. W. et al. Dysregulation of T(FH)-B-T(RM) lymphocyte cooperation is associated with unfavorable anti-PD-1 responses in EGFR-mutant lung cancer. Nat. Commun. 12, 6068 (2021).
Article CAS PubMed PubMed Central Google Scholar
Mami-Chouaib, F. et al. Resident memory T cells, critical components in tumor immunology. J. Immunother. Cancer 6, 87 (2018).
Article PubMed PubMed Central Google Scholar
Mathieu, M., Cotta-Grand, N., Daudelin, J. F., Thébault, P. & Labrecque, N. Notch signaling regulates PD-1 expression during CD8(+) T-cell activation. Immunol. Cell Biol. 91, 82–88 (2013).
Article CAS PubMed Google Scholar
Yu, W., Wang, Y. & Guo, P. Notch signaling pathway dampens tumor-infiltrating CD8(+) T cells activity in patients with colorectal carcinoma. Biomed. Pharmacother. 97, 535–542 (2018).
Article CAS PubMed Google Scholar
Choe, J. H. et al. SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma. Sci. Transl. Med. 13, eabe7378 (2021).
Roybal, K. T. et al. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164, 770–779 (2016).
Article CAS PubMed PubMed Central Google Scholar
Yu, S., Yi, M., Qin, S. & Wu, K. Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity. Mol. Cancer 18, 125 (2019).
Article PubMed PubMed Central CAS Google Scholar
Hyrenius-Wittsten, A. et al. SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models. Sci. Transl. Med. 13, eabd8836 (2021).
Amsen, D., Antov, A. & Flavell, R. A. The different faces of Notch in T-helper-cell differentiation. Nat. Rev. Immunol. 9, 116–124 (2009).
Article CAS PubMed Google Scholar
Kared, H. et al. Jagged2-expressing hematopoietic progenitors promote regulatory T cell expansion in the periphery through notch signaling. Immunity 25, 823–834 (2006).
Article CAS PubMed Google Scholar
Cahill, E. F., Tobin, L. M., Carty, F., Mahon, B. P. & English, K. Jagged-1 is required for the expansion of CD4+ CD25+ FoxP3+ regulatory T cells and tolerogenic dendritic cells by murine mesenchymal stromal cells. Stem Cell Res. Ther. 6, 19 (2015).
Article PubMed PubMed Central CAS Google Scholar
Samon, J. B. et al. Notch1 and TGFbeta1 cooperatively regulate Foxp3 expression and the maintenance of peripheral regulatory T cells. Blood 112, 1813–1821 (2008).
Article CAS PubMed PubMed Central Google Scholar
Charbonnier, L. M., Wang, S., Georgiev, P., Sefik, E. & Chatila, T. A. Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling. Nat. Immunol. 16, 1162–1173 (2015).
Article CAS PubMed PubMed Central Google Scholar
Zakiryanova, G. K. et al. Notch signaling defects in NK cells in patients with cancer. Cancer Immunol. Immunother. 70, 981–988 (2021).
Article CAS PubMed Google Scholar
Franklin, R. A. et al. The cellular and molecular origin of tumor-associated macrophages. Science 344, 921–925 (2014).
Article CAS PubMed PubMed Central Google Scholar
Ye, Y. C. et al. NOTCH Signaling via WNT regulates the proliferation of alternative, CCR2-independent tumor-associated macrophages in hepatocellular carcinoma. Cancer Res. 79, 4160–4172 (2019).
Article CAS PubMed Google Scholar
Liu, H. et al. Jagged1 promotes aromatase inhibitor resistance by modulating tumor-associated macrophage differentiation in breast cancer patients. Breast Cancer Res. Treat. 166, 95–107 (2017).
Article CAS PubMed Google Scholar
Palaga, T. et al. Notch signaling is activated by TLR stimulation and regulates macrophage functions. Eur. J. Immunol. 38, 174–183 (2008).
Article CAS PubMed Google Scholar
Boonyatecha, N., Sangphech, N., Wongchana, W., Kueanjinda, P. & Palaga, T. Involvement of Notch signaling pathway in regulating IL-12 expression via c-Rel in activated macrophages. Mol. Immunol. 51, 255–262 (2012).
Article CAS PubMed PubMed Central Google Scholar
Wang, Y. C. et al. Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res. 70, 4840–4849 (2010).
Article CAS PubMed Google Scholar
Zhao, J. L. et al. Forced activation of notch in macrophages represses tumor growth by upregulating miR-125a and disabling tumor-associated macrophages. Cancer Res. 76, 1403–1415 (2016).
Article CAS PubMed Google Scholar
Saleem, S. J. & Conrad, D. H. Hematopoietic cytokine-induced transcriptional regulation and Notch signaling as modulators of MDSC expansion. Int Immunopharmacol. 11, 808–815 (2011).
Article CAS PubMed Google Scholar
Wang, S. H. et al. The blockage of Notch signalling promoted the generation of polymorphonuclear myeloid-derived suppressor cells with lower immunosuppression. Eur. J. Cancer 68, 90–105 (2016).
Article CAS PubMed Google Scholar
Jiang, H. et al. Reduction of myeloid derived suppressor cells by inhibiting Notch pathway prevents the progression of endometriosis in mice model. Int. Immunopharmacol. 82, 106352 (2020).
Article CAS PubMed Google Scholar
Yang, Z. et al. Notch1 signaling in melanoma cells promoted tumor-induced immunosuppression via upregulation of TGF-β1. J. Exp. Clin. Cancer Res. 37, 1 (2018).
Article CAS PubMed PubMed Central Google Scholar
Sierra, R. A. et al. Anti-jagged immunotherapy inhibits MDSCs and overcomes tumor-induced tolerance. Cancer Res. 77, 5628–5638 (2017).
Article CAS PubMed PubMed Central Google Scholar
Caiado, F. et al. Bone marrow-derived CD11b+Jagged2+ cells promote epithelial-to-mesenchymal transition and metastasization in colorectal cancer. Cancer Res. 73, 4233–4246 (2013).
Article CAS PubMed Google Scholar
Sprouse, M. L. et al. PMN-MDSCs enhance CTC metastatic properties through reciprocal interactions via ROS/notch/nodal signaling. Int. J. Mol. Sci. 20, (2019).
Peng, D. et al. Myeloid-derived suppressor cells endow stem-like qualities to breast cancer cells through IL6/STAT3 and NO/NOTCH cross-talk signaling. Cancer Res. 76, 3156–3165 (2016).
Article CAS PubMed PubMed Central Google Scholar
Welte, T. et al. Oncogenic mTOR signalling recruits myeloid-derived suppressor cells to promote tumour initiation. Nat. Cell Biol. 18, 632–644 (2016).
Article CAS PubMed PubMed Central Google Scholar
Yang, M. et al. Tumour-associated neutrophils orchestrate intratumoural IL-8-driven immune evasion through Jagged2 activation in ovarian cancer. Br. J. Cancer 123, 1404–1416 (2020).
Article CAS PubMed PubMed Central Google Scholar
Hu, B. et al. Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling. Cell 149, 1207–1220 (2012).
Article CAS PubMed PubMed Central Google Scholar
Procopio, M. G. et al. Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation. Nat. Cell Biol. 17, 1193–1204 (2015).
Article CAS PubMed PubMed Central Google Scholar
Demehri, S., Turkoz, A. & Kopan, R. Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment. Cancer Cell 16, 55–66 (2009).
Article CAS PubMed PubMed Central Google Scholar
Peng, Y. et al. Direct contacts with colon cancer cells regulate the differentiation of bone marrow mesenchymal stem cells into tumor associated fibroblasts. Biochem. Biophys. Res. Commun. 451, 68–73 (2014).
Article CAS PubMed Google Scholar
Su, Q. et al. Jagged1 upregulation in prostate epithelial cells promotes formation of reactive stroma in the Pten null mouse model for prostate cancer. Oncogene 36, 618–627 (2017).
Article CAS PubMed Google Scholar
Tsuyada, A. et al. CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Cancer Res. 72, 2768–2779 (2012).
Article CAS PubMed PubMed Central Google Scholar
Liu, C. et al. LSD1 stimulates cancer-associated fibroblasts to drive Notch3-dependent self-renewal of liver cancer stem-like cells. Cancer Res 78, 938–949 (2018).
Article CAS PubMed Google Scholar
Du, Y. et al. Intracellular Notch1 signaling in cancer-associated fibroblasts dictates the plasticity and stemness of melanoma stem/initiating cells. Stem Cells 37, 865–875 (2019).
Article CAS PubMed PubMed Central Google Scholar
Boelens, M. C. et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 159, 499–513 (2014).
Article CAS PubMed PubMed Central Google Scholar
Pelon, F. et al. Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms. Nat. Commun. 11, 404 (2020).
Article CAS PubMed PubMed Central Google Scholar
Liubomirski, Y. et al. Notch-mediated tumor-stroma-inflammation networks promote invasive properties and CXCL8 expression in triple-negative breast cancer. Front Immunol. 10, 804 (2019).
Article CAS PubMed PubMed Central Google Scholar
Strell, C. et al. Impact of epithelial-stromal interactions on peritumoral fibroblasts in ductal carcinoma in situ. J. Natl Cancer Inst. 111, 983–995 (2019).
Article PubMed PubMed Central CAS Google Scholar
Gong, J. et al. Increased expression of Fibulin-1 is associated with hepatocellular carcinoma progression by regulating the notch signaling pathway. Front Cell Dev. Biol. 8, 478 (2020).
Article PubMed PubMed Central Google Scholar
Nandhu, M. S. et al. Development of a function-blocking antibody against Fibulin-3 as a targeted reagent for glioblastoma. Clin. Cancer Res. 24, 821–833 (2018).
Article CAS PubMed Google Scholar
Donovan, L. J., Cha, S. E., Yale, A. R., Dreikorn, S. & Miyamoto, A. Identification of a functional proprotein convertase cleavage site in microfibril-associated glycoprotein 2. Matrix Biol. 32, 117–122 (2013).
Article CAS PubMed Google Scholar
Gordon-Weeks, A. et al. Tumour-derived laminin α5 (LAMA5) promotes colorectal liver metastasis growth, branching angiogenesis and notch pathway inhibition. Cancers (Basel) 11, 630 (2019).
Ogawa, K. et al. Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis. Cancer Lett. 481, 63–75 (2020).
Article CAS PubMed PubMed Central Google Scholar
Kuhnert, F. et al. Dll4 blockade in stromal cells mediates antitumor effects in preclinical models of ovarian cancer. Cancer Res. 75, 4086–4096 (2015).
Article CAS PubMed Google Scholar
Xu, Z. et al. MMGZ01, an anti-DLL4 monoclonal antibody, promotes nonfunctional vessels and inhibits breast tumor growth. Cancer Lett. 372, 118–127 (2016).
Article CAS PubMed Google Scholar
Funahashi, Y. et al. A notch1 ectodomain construct inhibits endothelial notch signaling, tumor growth, and angiogenesis. Cancer Res. 68, 4727–4735 (2008).
Article CAS PubMed PubMed Central Google Scholar
Boareto, M., Jolly, M. K., Ben-Jacob, E. & Onuchic, J. N. Jagged mediates differences in normal and tumor angiogenesis by affecting tip-stalk fate decision. Proc. Natl Acad. Sci. USA 112, E3836–3844 (2015).
Article CAS PubMed PubMed Central Google Scholar
Banerjee, D. et al. Notch suppresses angiogenesis and progression of hepatic metastases. Cancer Res. 75, 1592–1602 (2015).
Article CAS PubMed PubMed Central Google Scholar
Banerjee, D. et al. High-dose radiation increases Notch1 in tumor vasculature. Int J. Radiat. Oncol. Biol. Phys. 106, 857–866 (2020).
Article CAS PubMed Google Scholar
Periz, G. & Fortini, M. E. Ca(2+)-ATPase function is required for intracellular trafficking of the Notch receptor in Drosophila. EMBO J. 18, 5983–5993 (1999).
Article CAS PubMed PubMed Central Google Scholar
Pagliaro, L., Marchesini, M. & Roti, G. Targeting oncogenic Notch signaling with SERCA inhibitors. J. Hematol. Oncol. 14, 8 (2021).
Article CAS PubMed PubMed Central Google Scholar
Malecki, M. J. et al. Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes. Mol. Cell Biol. 26, 4642–4651 (2006).
Article CAS PubMed PubMed Central Google Scholar
Roti, G. et al. Complementary genomic screens identify SERCA as a therapeutic target in NOTCH1 mutated cancer. Cancer Cell 23, 390–405 (2013).
Article CAS PubMed PubMed Central Google Scholar
Roti, G. et al. Leukemia-specific delivery of mutant NOTCH1 targeted therapy. J. Exp. Med. 215, 197–216 (2018).
Article CAS PubMed PubMed Central Google Scholar
Treiman, M., Caspersen, C. & Christensen, S. B. A tool coming of age: thapsigargin as an inhibitor of sarco-endoplasmic reticulum Ca(2+)-ATPases. Trends Pharm. Sci. 19, 131–135 (1998).
Article CAS PubMed Google Scholar
Jackisch, C. et al. Delayed micromolar elevation in intracellular calcium precedes induction of apoptosis in thapsigargin-treated breast cancer cells. Clin. Cancer Res. 6, 2844–2850 (2000).
CAS PubMed Google Scholar
Marchesini, M. et al. Blockade of oncogenic NOTCH1 with the SERCA inhibitor CAD204520 in T cell acute lymphoblastic leukemia. Cell Chem. Biol. 27, 678–697.e613 (2020).
Article CAS PubMed PubMed Central Google Scholar
Mumm, J. S. et al. A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol. Cell 5, 197–206 (2000).
Article CAS PubMed Google Scholar
Cousin, H., Abbruzzese, G., Kerdavid, E., Gaultier, A. & Alfandari, D. Translocation of the cytoplasmic domain of ADAM13 to the nucleus is essential for Calpain8-a expression and cranial neural crest cell migration. Dev. Cell 20, 256–263 (2011).
Article CAS PubMed PubMed Central Google Scholar
Saha, N., Robev, D., Himanen, J. P. & Nikolov, D. B. ADAM proteases: emerging role and targeting of the non-catalytic domains. Cancer Lett. 467, 50–57 (2019).
Article CAS PubMed PubMed Central Google Scholar
Murthy, A. et al. Notch activation by the metalloproteinase ADAM17 regulates myeloproliferation and atopic barrier immunity by suppressing epithelial cytokine synthesis. Immunity 36, 105–119 (2012).
Article CAS PubMed Google Scholar
Edwards, D. R., Handsley, M. M. & Pennington, C. J. The ADAM metalloproteinases. Mol. Asp. Med. 29, 258–289 (2008).
Article CAS Google Scholar
Lu, H. Y. et al. Novel ADAM-17 inhibitor ZLDI-8 inhibits the proliferation and metastasis of chemo-resistant non-small-cell lung cancer by reversing Notch and epithelial mesenchymal transition in vitro and in vivo. Pharm. Res. 148, 104406 (2019).
Article CAS Google Scholar
Yang, B. et al. MicroRNA-3163 targets ADAM-17 and enhances the sensitivity of hepatocellular carcinoma cells to molecular targeted agents. Cell Death Dis. 10, 784 (2019).
Article PubMed PubMed Central CAS Google Scholar
Guo, Z., Jin, X. & Jia, H. Inhibition of ADAM-17 more effectively down-regulates the Notch pathway than that of γ-secretase in renal carcinoma. J. Exp. Clin. Cancer Res. 32, 26 (2013).
Article CAS PubMed PubMed Central Google Scholar
Mullooly, M. et al. ADAM10: a new player in breast cancer progression? Br. J. Cancer 113, 945–951 (2015).
Article CAS PubMed PubMed Central Google Scholar
Kavian, N. et al. Targeting ADAM-17/notch signaling abrogates the development of systemic sclerosis in a murine model. Arthritis Rheum. 62, 3477–3487 (2010).
Article CAS PubMed Google Scholar
Fortini, M. E. Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling. Nat. Rev. Mol. Cell Biol. 3, 673–684 (2002).
Article CAS PubMed Google Scholar
Mumm, J. S. & Kopan, R. Notch signaling: from the outside. Dev. Biol. 228, 151–165 (2000).
Article CAS PubMed Google Scholar
Doody, R. S. et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N. Engl. J. Med. 369, 341–350 (2013).
Article CAS PubMed Google Scholar
Das, A. et al. A novel triazole, NMK-T-057, induces autophagic cell death in breast cancer cells by inhibiting γ-secretase-mediated activation of Notch signaling. J. Biol. Chem. 294, 6733–6750 (2019).
Article CAS PubMed PubMed Central Google Scholar
Sardesai, S. et al. A phase I study of an oral selective gamma secretase (GS) inhibitor RO4929097 in combination with neoadjuvant paclitaxel and carboplatin in triple negative breast cancer. Invest N. Drugs 38, 1400–1410 (2020).
Article CAS Google Scholar
Han, B. et al. Notch1 downregulation combined with interleukin-24 inhibits invasion and migration of hepatocellular carcinoma cells. World J. Gastroenterol. 21, 9727–9735 (2015).
Article CAS PubMed PubMed Central Google Scholar
Yong, Y. L. et al. Gamma-secretase complex-dependent intramembrane proteolysis of CD147 regulates the Notch1 signaling pathway in hepatocellular carcinoma. J. Pathol. 249, 255–267 (2019).
Article CAS PubMed Google Scholar
Pine, S. R. Rethinking gamma-secretase inhibitors for treatment of non-small-cell lung cancer: is notch the target? Clin. Cancer Res 24, 6136–6141 (2018).
Article CAS PubMed PubMed Central Google Scholar
Akiyoshi, T. et al. Gamma-secretase inhibitors enhance taxane-induced mitotic arrest and apoptosis in colon cancer cells. Gastroenterology 134, 131–144 (2008).
Article CAS PubMed Google Scholar
Cui, D. et al. Notch pathway inhibition using PF-03084014, a γ-secretase inhibitor (GSI), enhances the antitumor effect of docetaxel in prostate cancer. Clin. Cancer Res. 21, 4619–4629 (2015).
Article CAS PubMed PubMed Central Google Scholar
Gilbert, C. A., Daou, M. C., Moser, R. P. & Ross, A. H. Gamma-secretase inhibitors enhance temozolomide treatment of human gliomas by inhibiting neurosphere repopulation and xenograft recurrence. Cancer Res. 70, 6870–6879 (2010).
Article CAS PubMed PubMed Central Google Scholar
Messersmith, W. A. et al. A Phase I, dose-finding study in patients with advanced solid malignancies of the oral γ-secretase inhibitor PF-03084014. Clin. Cancer Res. 21, 60–67 (2015).
Article CAS PubMed Google Scholar
Tolcher, A. W. et al. Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. J. Clin. Oncol. 30, 2348–2353 (2012).
Article CAS PubMed PubMed Central Google Scholar
Xu, R. et al. Molecular and clinical effects of notch inhibition in glioma patients: a phase 0/i trial. Clin. Cancer Res 22, 4786–4796 (2016).
Article CAS PubMed PubMed Central Google Scholar
Aung, K. L. et al. A multi-arm phase I dose escalating study of an oral NOTCH inhibitor BMS-986115 in patients with advanced solid tumours. Invest N. Drugs 36, 1026–1036 (2018).
Article CAS Google Scholar
Pant, S. et al. A first-in-human phase I study of the oral Notch inhibitor, LY900009, in patients with advanced cancer. Eur. J. Cancer 56, 1–9 (2016).
Article CAS PubMed Google Scholar
Massard, C. et al. First-in-human study of LY3039478, an oral Notch signaling inhibitor in advanced or metastatic cancer. Ann. Oncol. 29, 1911–1917 (2018).
Article CAS PubMed Google Scholar
Fouladi, M. et al. Phase I trial of MK-0752 in children with refractory CNS malignancies: a pediatric brain tumor consortium study. J. Clin. Oncol. 29, 3529–3534 (2011).
Article CAS PubMed PubMed Central Google Scholar
Cook, N. et al. A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma. Br. J. Cancer 118, 793–801 (2018).
Article CAS PubMed PubMed Central Google Scholar
Lee, S. M. et al. Phase 2 study of RO4929097, a gamma-secretase inhibitor, in metastatic melanoma: SWOG 0933. Cancer 121, 432–440 (2015).
Article CAS PubMed Google Scholar
Diaz-Padilla, I. et al. A phase II study of single-agent RO4929097, a gamma-secretase inhibitor of Notch signaling, in patients with recurrent platinum-resistant epithelial ovarian cancer: a study of the Princess Margaret, Chicago and California phase II consortia. Gynecol. Oncol. 137, 216–222 (2015).
Article CAS PubMed Google Scholar
Strosberg, J. R. et al. A phase II study of RO4929097 in metastatic colorectal cancer. Eur. J. Cancer 48, 997–1003 (2012).
Kummar, S. et al. Clinical activity of the γ-secretase inhibitor PF-03084014 in adults with desmoid tumors (aggressive fibromatosis). J. Clin. Oncol. 35, 1561–1569 (2017).
Article CAS PubMed PubMed Central Google Scholar
Kang, J. H. et al. Gamma-secretase inhibitor reduces allergic pulmonary inflammation by modulating Th1 and Th2 responses. Am. J. Respir. Crit. Care Med. 179, 875–882 (2009).
Article CAS PubMed Google Scholar
Kukar, T. L. et al. Substrate-targeting gamma-secretase modulators. Nature 453, 925–929 (2008).
Article CAS PubMed PubMed Central Google Scholar
Golde, T. E., Koo, E. H., Felsenstein, K. M., Osborne, B. A. & Miele, L. γ-Secretase inhibitors and modulators. Biochim. Biophys. Acta 1828, 2898–2907 (2013).
Article CAS PubMed Google Scholar
Habets, R. A. et al. Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition. Sci. Transl. Med. 11, eaau6246 (2019).
Zhang, S. et al. A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling. Mol. Psychiatry 25, 603–613 (2020).
Article CAS PubMed Google Scholar
Soares, H. D. et al. The γ-secretase modulator, BMS-932481, modulates Aβ peptides in the plasma and cerebrospinal fluid of healthy volunteers. J. Pharm. Exp. Ther. 358, 138–150 (2016).
Article CAS Google Scholar
Murciano-Goroff, Y. R., Taylor, B. S., Hyman, D. M. & Schram, A. M. Toward a more precise future for oncology. Cancer Cell 37, 431–442 (2020).
Article CAS PubMed PubMed Central Google Scholar
Hann, C. L. et al. A phase 1 study evaluating rovalpituzumab tesirine in frontline treatment of patients with extensive-stage SCLC. J. Thorac. Oncol. 16, 1582–1588 (2021).
Article CAS PubMed Google Scholar
Simon, D. P., Giordano, T. J. & Hammer, G. D. Upregulated JAG1 enhances cell proliferation in adrenocortical carcinoma. Clin. Cancer Res 18, 2452–2464 (2012).
Article CAS PubMed Google Scholar
Santagata, S. et al. JAGGED1 expression is associated with prostate cancer metastasis and recurrence. Cancer Res 64, 6854–6857 (2004).
Article CAS PubMed Google Scholar
Masiero, M. et al. Development of therapeutic anti-JAGGED1 antibodies for cancer therapy. Mol. Cancer Ther. 18, 2030–2042 (2019).
Article CAS PubMed PubMed Central Google Scholar
Zheng, H. et al. Therapeutic antibody targeting tumor- and osteoblastic niche-derived Jagged1 sensitizes bone metastasis to chemotherapy. Cancer Cell 32, 731–747.e736 (2017).
Article CAS PubMed PubMed Central Google Scholar
Sabari, J. K., Lok, B. H., Laird, J. H., Poirier, J. T. & Rudin, C. M. Unravelling the biology of SCLC: implications for therapy. Nat. Rev. Clin. Oncol. 14, 549–561 (2017).
Article CAS PubMed PubMed Central Google Scholar
Puca, L. et al. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci. Transl. Med. 11, eaav0891 (2019).
Morgensztern, D. et al. Efficacy and safety of rovalpituzumab tesirine in third-line and beyond patients with DLL3-expressing, relapsed/refractory small-cell lung cancer: results from the phase II TRINITY study. Clin. Cancer Res. 25, 6958–6966 (2019).
Article CAS PubMed PubMed Central Google Scholar
Johnson, M. L. et al. Rovalpituzumab tesirine as a maintenance therapy after first-line platinum-based chemotherapy in patients with extensive-stage-SCLC: results from the phase 3 MERU study. J. Thorac. Oncol. 16, 1570–1581 (2021).
Article CAS PubMed Google Scholar
Blackhall, F. et al. Efficacy and safety of rovalpituzumab tesirine compared with topotecan as second-line therapy in DLL3-High SCLC: results from the phase 3 TAHOE study. J. Thorac. Oncol. 16, 1547–1558 (2021).
Article CAS PubMed Google Scholar
Malhotra, J. et al. A phase 1-2 study of rovalpituzumab tesirine in combination with nivolumab plus or minus ipilimumab in patients with previously treated extensive-stage SCLC. J. Thorac. Oncol. 16, 1559–1569 (2021).
Article CAS PubMed Google Scholar
Spino, M. et al. Cell surface Notch ligand DLL3 is a therapeutic target in isocitrate dehydrogenase-mutant glioma. Clin. Cancer Res. 25, 1261–1271 (2019).
Article CAS PubMed Google Scholar
Morgensztern, D. et al. SC-002 in patients with relapsed or refractory small cell lung cancer and large cell neuroendocrine carcinoma: Phase 1 study. Lung Cancer 145, 126–131 (2020).
Article PubMed Google Scholar
Ridgway, J. et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444, 1083–1087 (2006).
Article CAS PubMed Google Scholar
Liu, S. K. et al. Delta-like ligand 4-notch blockade and tumor radiation response. J. Natl Cancer Inst. 103, 1778–1798 (2011).
Article CAS PubMed Google Scholar
Chiorean, E. G. et al. A phase i first-in-human study of enoticumab (REGN421), a fully human delta-like ligand 4 (Dll4) monoclonal antibody in patients with advanced solid tumors. Clin. Cancer Res. 21, 2695–2703 (2015).
Article CAS PubMed Google Scholar
Smith, D. C. et al. A phase I dose escalation and expansion study of the anticancer stem cell agent demcizumab (anti-DLL4) in patients with previously treated solid tumors. Clin. Cancer Res. 20, 6295–6303 (2014).
Article CAS PubMed Google Scholar
Coleman, R. L. et al. Demcizumab combined with paclitaxel for platinum-resistant ovarian, primary peritoneal, and fallopian tube cancer: The SIERRA open-label phase Ib trial. Gynecol. Oncol. 157, 386–391 (2020).
Article CAS PubMed Google Scholar
Li, Y. et al. ABT-165, a dual variable domain immunoglobulin (DVD-Ig) targeting DLL4 and VEGF, demonstrates superior efficacy and favorable safety profiles in preclinical models. Mol. Cancer Ther. 17, 1039–1050 (2018).
Article CAS PubMed Google Scholar
Jimeno, A. et al. A first-in-human phase 1a study of the bispecific anti-DLL4/anti-VEGF antibody navicixizumab (OMP-305B83) in patients with previously treated solid tumors. Invest N. Drugs 37, 461–472 (2019).
Article CAS Google Scholar
Long, J. et al. JAG2/Notch2 inhibits intervertebral disc degeneration by modulating cell proliferation, apoptosis, and extracellular matrix. Arthritis Res. Ther. 21, 213 (2019).
Article PubMed PubMed Central Google Scholar
Guo, P. et al. Endothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppression. J. Clin. Invest. 127, 4242–4256 (2017).
Article PubMed PubMed Central Google Scholar
Yang, Y. et al. The Notch ligand Jagged2 promotes lung adenocarcinoma metastasis through a miR-200-dependent pathway in mice. J. Clin. Invest. 121, 1373–1385 (2011).
Article CAS PubMed PubMed Central Google Scholar
Chen, Y. T. et al. Jagged2 progressively increased expression from Stage I to III of Bladder Cancer and Melatonin-mediated downregulation of Notch/Jagged2 suppresses the Bladder Tumorigenesis via inhibiting PI3K/AKT/mTOR/MMPs signaling. Int J. Biol. Sci. 16, 2648–2662 (2020).
Article CAS PubMed PubMed Central Google Scholar
Santos, M. A. et al. Notch1 engagement by Delta-like-1 promotes differentiation of B lymphocytes to antibody-secreting cells. Proc. Natl Acad. Sci. USA 104, 15454–15459 (2007).
Article CAS PubMed PubMed Central Google Scholar
Grabher, C., von Boehmer, H. & Look, A. T. Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat. Rev. Cancer 6, 347–359 (2006).
Article CAS PubMed Google Scholar
Liao, W. et al. Antitumor activity of Notch‑1 inhibition in human colorectal carcinoma cells. Oncol. Rep. 39, 1063–1071 (2018).
CAS PubMed Google Scholar
Purow, B. W. et al. Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res. 65, 2353–2363 (2005).
Article CAS PubMed Google Scholar
Ferrarotto, R. et al. Activating NOTCH1 mutations define a distinct subgroup of patients with adenoid cystic carcinoma who have poor prognosis, propensity to bone and liver metastasis, and potential responsiveness to Notch1 inhibitors. J. Clin. Oncol. 35, 352–360 (2017).
Article CAS PubMed Google Scholar
Choi, B. Y. et al. Inhibition of Notch1 induces population and suppressive activity of regulatory T cell in inflammatory arthritis. Theranostics 8, 4795–4804 (2018).
Article CAS PubMed PubMed Central Google Scholar
Magee, C. N. et al. Notch-1 inhibition promotes immune regulation in transplantation via regulatory T cell-dependent mechanisms. Circulation 140, 846–863 (2019).
Article CAS PubMed PubMed Central Google Scholar
Lee, S. Y. et al. Gain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphoma. Cancer Sci. 100, 920–926 (2009).
Article CAS PubMed Google Scholar
Mazur, P. K. et al. Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma. Proc. Natl Acad. Sci. USA 107, 13438–13443 (2010).
Article CAS PubMed PubMed Central Google Scholar
Massi, D. et al. Evidence for differential expression of Notch receptors and their ligands in melanocytic nevi and cutaneous malignant melanoma. Mod. Pathol. 19, 246–254 (2006).
Article CAS PubMed Google Scholar
Lin, L. et al. Targeting specific regions of the Notch3 ligand-binding domain induces apoptosis and inhibits tumor growth in lung cancer. Cancer Res. 70, 632–638 (2010).
Article CAS PubMed PubMed Central Google Scholar
Yamaguchi, N. et al. NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells. Cancer Res. 68, 1881–1888 (2008).
Article CAS PubMed Google Scholar
Hu, Z. I. et al. A randomized phase II trial of nab-paclitaxel and gemcitabine with tarextumab or placebo in patients with untreated metastatic pancreatic cancer. Cancer Med. 8, 5148–5157 (2019).
Article CAS PubMed PubMed Central Google Scholar
Smith, D. C. et al. A phase 1 dose escalation and expansion study of Tarextumab (OMP-59R5) in patients with solid tumors. Invest N. Drugs 37, 722–730 (2019).
Article CAS Google Scholar
Rosen, L. S. et al. A phase I, dose-escalation study of PF-06650808, an anti-Notch3 antibody-drug conjugate, in patients with breast cancer and other advanced solid tumors. Invest N. Drugs 38, 120–130 (2020).
Article CAS Google Scholar
Harrison, H. et al. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res. 70, 709–718 (2010).
Article CAS PubMed PubMed Central Google Scholar
Xiu, M. et al. Targeting Notch4 in cancer: molecular mechanisms and therapeutic perspectives. Cancer Manag. Res. 13, 7033–7045 (2021).
Article PubMed PubMed Central Google Scholar
Nam, Y., Sliz, P., Song, L., Aster, J. C. & Blacklow, S. C. Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell 124, 973–983 (2006).
Article CAS PubMed Google Scholar
Tamura, K. et al. Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H). Curr. Biol. 5, 1416–1423 (1995).
Article CAS PubMed Google Scholar
Hurtado, C. et al. Disruption of NOTCH signaling by a small molecule inhibitor of the transcription factor RBPJ. Sci. Rep. 9, 10811 (2019).
Article PubMed PubMed Central CAS Google Scholar
Astudillo, L. et al. The small molecule IMR-1 inhibits the notch transcriptional activation complex to suppress tumorigenesis. Cancer Res. 76, 3593–3603 (2016).
Article CAS PubMed PubMed Central Google Scholar
Lehal, R. et al. Pharmacological disruption of the Notch transcription factor complex. Proc. Natl Acad. Sci. USA 117, 16292–16301 (2020).
Article CAS PubMed PubMed Central Google Scholar
Koch, U. & Radtke, F. Notch and cancer: a double-edged sword. Cell Mol. Life Sci. 64, 2746–2762 (2007).
Article CAS PubMed Google Scholar
Zage, P. E. et al. Notch pathway activation induces neuroblastoma tumor cell growth arrest. Pediatr. Blood Cancer 58, 682–689 (2012).
Article PubMed Google Scholar
Yu, X. M., Phan, T., Patel, P. N., Jaskula-Sztul, R. & Chen, H. Chrysin activates Notch1 signaling and suppresses tumor growth of anaplastic thyroid carcinoma in vitro and in vivo. Cancer 119, 774–781 (2013).
Article CAS PubMed Google Scholar
Patel, P. N., Yu, X. M., Jaskula-Sztul, R. & Chen, H. Hesperetin activates the Notch1 signaling cascade, causes apoptosis, and induces cellular differentiation in anaplastic thyroid cancer. Ann. Surg. Oncol. 21, S497–504 (2014).
Article PubMed Google Scholar
Li, K. et al. Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3. J. Biol. Chem. 283, 8046–8054 (2008).
Article CAS PubMed Google Scholar
Demitrack, E. S. & Samuelson, L. C. Notch as a Driver of Gastric Epithelial Cell Proliferation. Cell Mol. Gastroenterol. Hepatol. 3, 323–330 (2017).
Article PubMed PubMed Central Google Scholar
Real, P. J. et al. Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat. Med. 15, 50–58 (2009).
Article CAS PubMed Google Scholar
Luistro, L. et al. Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res. 69, 7672–7680 (2009).
Article CAS PubMed PubMed Central Google Scholar
Govaerts, I. et al. PSEN1-selective gamma-secretase inhibition in combination with kinase or XPO-1 inhibitors effectively targets T cell acute lymphoblastic leukemia. J. Hematol. Oncol. 14, 97 (2021).
Article CAS PubMed PubMed Central Google Scholar
Ito, T. Intratumoral heterogeneity of Notch1 expression in small cell lung cancer. J. Thorac. Dis. 10, 1272–1275 (2018).
Article PubMed PubMed Central Google Scholar
Marx, V. Method of the Year: spatially resolved transcriptomics. Nat. Methods 18, 9–14 (2021).
Article CAS PubMed Google Scholar
Joutel, A. Prospects for diminishing the impact of nonamyloid small-vessel diseases of the brain. Annu. Rev. Pharm. Toxicol. 60, 437–456 (2020).
Article CAS Google Scholar
Matsuda, M. et al. Recapitulating the human segmentation clock with pluripotent stem cells. Nature 580, 124–129 (2020).
Article CAS PubMed Google Scholar
Simpson, M. A. et al. Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat. Genet. 43, 303–305 (2011).
Article CAS PubMed Google Scholar
Isidor, B. et al. Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat. Genet. 43, 306–308 (2011).
Article CAS PubMed Google Scholar
Fukushima, H. et al. NOTCH2 Hajdu-Cheney Mutations Escape SCF-Dependent Proteolysis to Promote Osteoporosis. Mol. Cell 68, 645–658.e5 (2017).
Article CAS PubMed PubMed Central Google Scholar
Luxán, G. et al. Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy. Nat. Med. 19, 193–201 (2013).
Article PubMed CAS Google Scholar
Towbin, J. A., Lorts, A. & Jefferies, J. L. Left ventricular non-compaction cardiomyopathy. Lancet 386, 813–825 (2015).
Article PubMed Google Scholar
Stittrich, A.-B. et al. Mutations in NOTCH1 cause Adams-Oliver syndrome. Am. J. Hum. Genet. 95, 275–284 (2014).
Article CAS PubMed PubMed Central Google Scholar
Hassed, S. J. et al. RBPJ mutations identified in two families affected by Adams-Oliver syndrome. Am. J. Hum. Genet. 91, 391–395 (2012).
Article CAS PubMed PubMed Central Google Scholar
Nus, M. et al. Diet-induced aortic valve disease in mice haploinsufficient for the Notch pathway effector RBPJK/CSL. Arterioscler Thromb. Vasc. Biol. 31, 1580–1588 (2011).
Article CAS PubMed Google Scholar
MacGrogan, D. et al. Sequential ligand-dependent notch signaling activation regulates valve primordium formation and morphogenesis. Circ. Res. 118, 1480–1497 (2016).
Article CAS PubMed Google Scholar
Wang, Y. et al. Notch-Tnf signalling is required for development and homeostasis of arterial valves. Eur. Heart J. 38, 675–686 (2017).
PubMed Google Scholar
Ikeda, M. et al. Genetic evidence for association between NOTCH4 and schizophrenia supported by a GWAS follow-up study in a Japanese population. Mol. Psychiatry 18, 636–638 (2013).
Article CAS PubMed Google Scholar
Zhang, Y. et al. Convergent lines of evidence support as a schizophrenia risk gene. J. Med. Genet. 58, 666–678 (2021).
Article CAS PubMed Google Scholar
Morris, H. E., Neves, K. B., Montezano, A. C., MacLean, M. R. & Touyz, R. M. Notch3 signalling and vascular remodelling in pulmonary arterial hypertension. Clin. Sci. 133, 2481–2498 (2019).
Article CAS Google Scholar
Li, X. et al. Notch3 signaling promotes the development of pulmonary arterial hypertension. Nat. Med. 15, 1289–1297 (2009).
Article CAS PubMed PubMed Central Google Scholar
Zhang, Y. et al. Notch signaling is a critical regulator of allogeneic CD4+ T-cell responses mediating graft-versus-host disease. Blood 117, 299–308 (2011).
Article CAS PubMed PubMed Central Google Scholar
Siveke, J. T. et al. Notch signaling is required for exocrine regeneration after acute pancreatitis. Gastroenterology 134, 544–555 (2008).
Article CAS PubMed Google Scholar
Golson, M. L., Loomes, K. M., Oakey, R. & Kaestner, K. H. Ductal malformation and pancreatitis in mice caused by conditional Jag1 deletion. Gastroenterology 136, 1761–1771.e1 (2009).
Article CAS PubMed Google Scholar
Zhang, X. et al. Inhibition of Notch activity promotes pancreatic cytokeratin 5-positive cell differentiation to beta cells and improves glucose homeostasis following acute pancreatitis. Cell Death Dis. 12, 867 (2021).
Article CAS PubMed PubMed Central Google Scholar
John, G. R. et al. Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat. Med. 8, 1115–1121 (2002).
Article CAS PubMed Google Scholar
Seifert, T., Bauer, J., Weissert, R., Fazekas, F. & Storch, M. K. Notch1 and its ligand Jagged1 are present in remyelination in a T-cell- and antibody-mediated model of inflammatory demyelination. Acta Neuropathol. 113, 195–203 (2007).
Article CAS PubMed Google Scholar
Zhang, Y. et al. Notch1 signaling plays a role in regulating precursor differentiation during CNS remyelination. Proc. Natl Acad. Sci. USA 106, 19162–19167 (2009).
Article CAS PubMed PubMed Central Google Scholar
Mu, X. et al. The role of Notch signaling in muscle progenitor cell depletion and the rapid onset of histopathology in muscular dystrophy. Hum. Mol. Genet. 24, 2923–2937 (2015).
Article CAS PubMed PubMed Central Google Scholar
Vieira, N. M. et al. Jagged 1 rescues the Duchenne muscular dystrophy phenotype. Cell 163, 1204–1213 (2015).
Article CAS PubMed PubMed Central Google Scholar
Tracy, M. R., Dormans, J. P. & Kusumi, K. Klippel-Feil syndrome: clinical features and current understanding of etiology. Clin. Orthop. Relat. Res. 424, 183–190 (2004).
Article Google Scholar
Karaca, E. et al. Rare variants in the notch signaling pathway describe a novel type of autosomal recessive Klippel-Feil syndrome. Am. J. Med. Genet. A 167A, 2795–2799 (2015).
Article PubMed PubMed Central CAS Google Scholar
Petruccelli, E. et al. Alcohol activates Scabrous-notch to influence associated memories. Neuron 100, 1209–1223 (2018).
Article CAS PubMed PubMed Central Google Scholar
Rosati, E. et al. Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. Blood 113, 856–865 (2009).
Article CAS PubMed Google Scholar
Papayannidis, C. et al. A Phase 1 study of the novel gamma-secretase inhibitor PF-03084014 in patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Blood Cancer J. 5, e350 (2015).
Article CAS PubMed PubMed Central Google Scholar
Peereboom, D. M. et al. A phase II and pharmacodynamic Trial of RO4929097 for patients with recurrent/progressive glioblastoma. Neurosurgery 88, 246–251 (2021).
Article PubMed Google Scholar
Krop, I. et al. Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors. J. Clin. Oncol. 30, 2307–2313 (2012).
Article CAS PubMed Google Scholar
Schott, A. F. et al. Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors. Clin. Cancer Res. 19, 1512–1524 (2013).
Article CAS PubMed PubMed Central Google Scholar
Mir, O. et al. Notch pathway inhibition with LY3039478 in soft tissue sarcoma and gastrointestinal stromal tumours. Eur. J. Cancer 103, 88–97 (2018).
Article CAS PubMed Google Scholar
Azaro, A. et al. Phase 1 study of 2 high dose intensity schedules of the pan-Notch inhibitor crenigacestat (LY3039478) in combination with prednisone in patients with advanced or metastatic cancer. Invest N. Drugs 39, 193–201 (2021).
Article CAS Google Scholar
Borthakur, G. et al. Phase 1 study to evaluate Crenigacestat (LY3039478) in combination with dexamethasone in patients with T-cell acute lymphoblastic leukemia and lymphoma. Cancer 127, 372–380 (2021).
Article CAS PubMed Google Scholar
Azaro, A. et al. A phase 1b study of the Notch inhibitor crenigacestat (LY3039478) in combination with other anticancer target agents (taladegib, LY3023414, or abemaciclib) in patients with advanced or metastatic solid tumors. Invest N. Drugs 39, 1089–1098 (2021).
Article CAS Google Scholar
Rudin, C. M. et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol. 18, 42–51 (2017).
Article CAS PubMed Google Scholar
McKeage, M. J. et al. Phase IB trial of the anti-cancer stem cell DLL4-binding agent demcizumab with pemetrexed and carboplatin as first-line treatment of metastatic non-squamous NSCLC. Target Oncol. 13, 89–98 (2018).
Article PubMed Google Scholar

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 62131009, 82072597, 81874120, and 82073370).

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These authors contributed equally: Binghan Zhou, Wanling Lin, Yaling Long

Authors and Affiliations

Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China
Binghan Zhou, Wanling Lin, Yaling Long, Yunkai Yang, Huan Zhang, Kongming Wu & Qian Chu

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Binghan Zhou
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Wanling Lin
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Yaling Long
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Yunkai Yang
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Huan Zhang
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Kongming Wu
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Qian Chu
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Contributions

Q.C. conceptualized this review. B.Z. and W.L. primarily searched for the papers and made the outline. B.Z., W.L., and Y.L. drafted the manuscript and drew the figures. Y.Y. edited the language. H.Z. helped with paper searching. Q.C. and K.W. provided helpful suggestions on the structure and content of this review. All authors revised the manuscript. All authors have read and approved the article.

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Correspondence to Qian Chu.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Figures were created with biorender.com.

Supplementary information

Supplementary Table1. The role of NOTCH signaling in developmental processes

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Zhou, B., Lin, W., Long, Y. et al. Notch signaling pathway: architecture, disease, and therapeutics. Sig Transduct Target Ther 7, 95 (2022). https://doi.org/10.1038/s41392-022-00934-y

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Received: 23 November 2021
Revised: 16 February 2022
Accepted: 16 February 2022
Published: 24 March 2022
DOI: https://doi.org/10.1038/s41392-022-00934-y

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Abstract

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Introduction

A brief history of notch signaling

The architecture of notch signaling

The receptors and ligands of NOTCH signaling

The canonical NOTCH signaling pathway

The noncanonical NOTCH signaling pathway

The mechanisms regulating NOTCH signaling

Glycosylation

Receptor trafficking

Ligand ubiquitylation

Cis-inhibition

Other regulatory mechanisms

Notch signaling in organ development and repair

NOTCH and somitogenesis

NOTCH and skeleton

NOTCH and cardiomyogenesis

NOTCH and the vasculature

NOTCH and the hemopoietic system

NOTCH and the liver

NOTCH and the gastrointestinal tract

NOTCH and the nervous system

NOTCH and other organs or systems

Notch signaling in noncancerous diseases

Diseases associated with abnormal expression of NOTCH signaling related to mutations

CADASIL

Alagille syndrome

Congenital scoliosis

Diseases associated with abnormal expression of NOTCH signaling not related to mutations

Nonalcoholic steatohepatitis

Osteoarthritis

Lung-related diseases

Other diseases

Notch signaling in cancers

NOTCH as an oncogene in cancers

Hematological malignancies

Lung adenocarcinoma

Colorectal cancer

Breast cancer

Ovarian cancer

Hepatocellular carcinoma

Glioma

Other cancers

NOTCH as a tumor suppressor in cancers

Neuroendocrine tumors

Squamous cell cancers

Pancreatic ductal carcinoma

NOTCH signaling in the tumor microenvironment

NOTCH signaling in immune cells

Dendritic cells

CD8+ T cells

CD4+ T cells, B cells, and NK cells

Tumor-associated macrophages

Myeloid-derived suppressor cells

Tumor-associated neutrophils

NOTCH signaling in cancer-associated fibroblasts and the extracellular matrix

NOTCH signaling in the tumor vasculature

Notch-targeted therapies

Cleavage inhibitors

S1 cleavage

S2 cleavage

S3 cleavage

γ-Secretase inhibitors

γ-Secretase modulators

Antibody-drug conjugates

Antibodies against ligands

JAG1

DLL3

DLL4

JAG2/DLL1

Antibodies against receptors

NOTCH1

NOTCH2/NOTCH3

NOTCH4

Transcription blockers